Renin inhibitors containing C-termini derived from mercaptoheterocycles.

A series of transition-state analogues having heterocyclythio C-termini has been synthesized and evaluated for inhibition of human renin. Addition of mercaptoheterocycles to a chiral Boc-amino epoxide intermediate led, after several steps, to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. Oxidation of the thioether to sulfone was also investigated. Several of the compounds, especially those derived from N1-substituted-5-mercaptotetrazoles or N4-substituted-3-mercapto-5-(trifluoromethyl)-1,2,4-triazoles, were moderately potent inhibitors of human plasma renin, having IC50 values of 30-40 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys at 0.3-1.2 mg/kg, they reduced plasma renin activity by 75-98%. However, this inhibition and the accompanying drop in blood pressure were of short duration.     

Neonatal stroke: Clinical characteristics and cerebral blood flow velocity measurements

The clinical courses of 8 term infants with focal cerebral infarction or neonatal stroke were studied to determine whether such infants can be identified by current markers of perinatal distress, and whether changes in cerebral blood flow velocity (CBFV) occur during the acute phase of the disease. CBFV was measured from the middle cerebral artery (MCA) and anterior cerebral artery (ACA) utilizing duplex Doppler. Seven of the 8 patients required no resuscitation in the delivery room; 1 infant required brief bag and mask ventilation. No infant had evidence of severe fetal acidemia (i.e., cord pH <7). All 8 infants were initially admitted to the newborn nursery. Infants were identified on the basis of abnormal clinical findings observed during the first 48 hours: seizures (n = 6) and hypotonia and apnea (n = 2). Serum electrolytes, calcium, magnesium, and glucose levels were normal, and the sepsis evaluation including a spinal tap was sterile in all patients. Neuroimaging revealed nonhemorrhagic left focal MCA infarction (n = 6) and right focal MCA infarction (n = 2). Duplex Doppler demonstrated transient ipsilateral decreases in CBFV as compared to the contralateral unaffected side at clinical presentation in 4 infants. In 2 of these infants the decrease in CBFV involved both the MCA and ACA, and in 2 infants, only the MCA vessels. These side-to-side differences were not present at subsequent CBFV measurements. The data indicate that infants who develop neonatal stroke cannot be distinguished from infants who do not develop the lesion by current markers of perinatal distress. Because neonatal stroke frequently occurs as an unanticipated event, prevention may not be possible.     

The nature and course of cystic pancreatic lesions diagnosed by ultrasound

To determine the nature and course of cystic pancreatic lesions, we reviewed the records of 93 patients who were followed up with serial ultrasound until resolution occurred or definitive therapy was given. Initially, 105 cystic lesions were seen. Single cysts occurred in 83 patients and multiple cysts in ten. Eight patients had two cysts and two patients had three. Twenty-one patients had a single ultrasound examination and 72 had two or more examinations. Spontaneous resolution occurred in 29 of (28%) 105 cysts in 24 patients. In 46 patients, 53 pseudocysts were found at operation or autopsy. Five patients had pancreatic abscesses. Two patients became unavailable for follow-up and three refused surgery. The results of one examination were false negative. Twelve patients had false-positive ultrasound results. Factors influencing the likelihood of spontaneous resolution included initial cyst size, subsequent increase in size, multiple cysts, and the presence of calcifications. This study confirms the usefulness of serial ultrasound scans in determining the nature and necessity for treatment of cystic lesions of the pancreas.     

Cholecystectomy in cirrhotic patients: A formidable operation

Cholecystectomy and common bile duct exploration in cirrhotic patients is associated with an 83 percent mortality if prothrombin time is prolonged 2.5 seconds over control. The causes of death are related to complications of liver disease such as hepatic encephalopathy, ascites, sepsis and hemorrhage. If the prothrombin time is prolonged, major intraoperative blood loss can be anticipated, and blood and plasma transfusion requirements may be massive. Jaundice in the presence of cirrhosis requires careful preoperative evaluation and is most frequently due to hepatocellular disease rather than extrahepatic biliary obstruction. Cholecystectomy and common duct exploration in cirrhotic patients should be performed only for life-threatening complications of biliary tract disease such as empyema, perforation and ascending cholangitis.     

Birth weight and systemic lupus erythematosus

The fetal environment may be a contributing factor in the etiology of some adult diseases. This study examined whether birth weight, birth length and gestational age are associated with the subsequent development of systemic lupus erythematosus (SLE). The Marshfield Clinic Lupus Registry was searched to identify patients who were born at Saint Joseph's Hospital in Marshfield, Wisconsin, USA. Birth data on each case and five age-, sex-, and race-matched controls were recorded from medical and delivery room register records. Perinatal data were obtained for 23 cases and 115 controls. The unadjusted mean birth weight was similar for cases (3407 +/- 581 g) and controls (3422 +/- 514 g). Birth length was not different between groups. Birth weight adjusted for gestational age, analysed by conditional logistic regression, was not statistically significantly different between groups. We concluded that birth weight and length were similar among SLE cases and controls, suggesting that these perinatal characteristics are not associated with subsequent SLE.     

Evidence for direct action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thymic epithelium

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targets within the immune system to produce a characteristic profile of pathologic responses typified by thymic atrophy, suppressed cellular immunity, and inhibition of antibody production to T-lymphocyte-dependent antigens. Studies in inbred mice differing in sensitivity to TCDD indicate that TCDD-induced thymic atrophy is mediated by a receptor protein (designated the Ah receptor). To study the cellular and molecular basis for TCDD-induced thymic atrophy, primary cultures of thymic epithelial (TE) cells were established from C57BL/6 mice, a strain sensitive to TCDD. Treatment of TE monolayers with TCDD (0.1 to 10 nM) resulted in the altered maturation of cocultured syngeneic thymocytes as judged by suppression (40% of control at 10 nM TCDD) of TE-dependent responsiveness of thymocytes to the mitogens concanavalin A and phytohemagglutinin. TE-conditioned medium enhanced the mitogen responsiveness of thymocytes three- to four-fold; however, the enhanced mitogen response mediated by the TE-conditioned medium was not suppressed in thymocytes incubated in medium collected from TCDD-treated cultures or in TE-conditioned medium to which TCDD (10 nM) had been added directly. The suppression of TE-dependent maturation of thymocytes was concentration dependent (EC50 approximately 1 nM) and stereospecific, suggesting involvement of the Ah receptor. The Ah receptor in cytosol fractions from cultured TE cells was measured directly and was found to be present at a concentration 3 and 3.5 times greater than that measured in whole thymus and thymocytes, respectively. The results of this study indicate that TCDD can act directly on epithelial target cells in the thymus: one consequence of this action appears to be the altered thymus-dependent maturation of T-lymphocyte precursors, mediated through direct cell-cell contact between thymocytes and TE cells.     

Subdural Empyema

Opinion statement Subdural empyema represents loculated infection between the outermost layer of the meninges, the dura, and the arachnoid. The empyema may develop intracranially or in the spinal canal. Intracranial subdural empyema is most frequently a complication of sinusitis or, less frequently, otitis or neurosurgical procedures. Spinal subdural empyema is rare and may result from hematogenous infection or spread of infection from osteomyelitis. The most common organisms in intracranial subdural empyema are anaerobic and microaerophilic streptococci, in particular those of the Streptococcus milleri group (S. milleri and Streptococcus anginosus). Staphylococcus aureus is present in a minority of cases, and multiple additional organisms, including Gramnegative organisms, such as Escherichia coli, and anaerobic organisms, such as Bacteroides, may be present. Pseudomonas aeruginosa or Staphylococcus epidermidis may be present in cases related to neurosurgical procedures, and Salmonella species have been detected in patients with advanced AIDS; multiple organisms may be present simultaneously. Spinal subdural empyemas are almost invariably caused by streptococci or by S. aureus. Subdural empyema—whether it occurs in the skull or the spinal canal—may cause rapid compression of the brain or spinal cord, and represents an extreme medical and neurosurgical emergency. The diagnostic procedure of choice for intracranial and spinal subdural empyema is MRI with gadolinium enhancement. Computed tomography scan may miss intracranial subdural empyemas detectable by MRI. Conversely, occasion spinal subdural empyemas may be detected by CT myelography where MRI is negative. Treatment in virtually all cases of intracranial or spinal subdural empyema requires prompt surgical drainage and antibiotic therapy. Pus from the empyema should always be sent for anaerobic, as well as aerobic, culture. Because intracranial subdural empyemas may contain multiple organisms, provisional antibiotic therapy of intracranial subdural empyema, where the organism is unknown, should be directed against S. aureus, microaerophilic and anaerobic streptococci, and Gram-negative organisms. Antibiotics should include 1) nafcillin, oxacillin, or vancomycin; plus 2) a third generation cephalosporin; plus 3) metronidazole. Provisional antibiotic therapy of spinal subdural empyemas should be directed against S. aureus and streptococci, and should include nafcillin, oxacillin, or vancomycin. Morbidity and mortality in intracranial and spinal subdural empyema relate directly to the delay in institution of therapy. Both conditions should, thus, be treated with great urgency.     

Measuring disease frequency in the Marshfield Epidemiologic Study Area (MESA)

The Marshfield Epidemiologic Study Area (MESA) is a rare resource for population-based health and medical research developed at Marshfield Clinic Research Foundation. Because of high population coverage and health event capture, MESA is particularly useful for determining the frequency of disease in the general population. A substantial proportion of MESA-based publications appearing in the peer reviewed literature have reported incidence or prevalence rates of disease or disease-related factors. This paper reviews the first 10 years of MESA's support of meaningful inquiry into the frequency of disease occurrence, and briefly reports on the data and methods used for such calculations using selected chronic diseases as examples. Limitations of MESA estimates are discussed as are alternate methods. Compared to limited data published for the selected conditions, occurrence rates in MESA based on diagnostic codes and general validation rules only appear somewhat high, although the observed temporal trends and relationships with demographics are consistent. Rich clinical data sources are available to be linked with MESA to improve the specificity of case ascertainment, as is typically done for disease-specific publications from MESA.