Clinical course and pancreas parenchyma sparing surgical treatment of severe pancreatic trauma.

INTRODUCTION: Pancreatic trauma (PT) involving the main pancreatic duct is rare, but represents a challenging clinical problem with relevant morbidity and mortality. It is generally classified according to the American Association for the Surgery of Trauma (AAST) and often presents as concomitant injury in blunt or penetrating abdominal trauma. Diagnosis may be delayed because of a lack of clinical or radiological manifestation. Treatment options for main pancreatic duct injuries comprise highly complex surgical procedures. PATIENTS AND METHODS: We retrospectively analyzed clinical data from 12 patients who underwent surgery in two tertiary centers in Germany during 2003-2016 for grade III-V PT with affection of the main pancreatic duct, according to the AAST classification. RESULTS: The median age was 23 (range: 7-44) years. In nine patients blunt abdominal trauma was the reason for PT, whereas penetrating trauma only occurred in three patients. MRI outperformed classical trauma CT imaging with regard to detection of duct involvement. Complex procedures as i.e. an emergency pancreatic head resection, distal pancreatectomy or parenchyma sparing pancreatogastrostomy were performed. Compared to elective pancreatic surgery the complication rate in the emergency setting was higher. Yet, parenchyma-sparing procedures demonstrated safety. CONCLUSIONS: Often extension of diagnostics including MRI and/or ERP at an early stage is necessary to guide clinical decision-making. If, due to main duct injuries, surgical therapy for PT is required, we suggest consideration of an organ preservative pancreatogastrostomy in grade III/IV trauma of the pancreatic body or tail.

Diagnostic and therapeutic use of membrane proteins in cancer cells.

As proteomics technologies develop, increasing number of membrane-associated proteins specific for cancer cells are being discovered. These proteins are of great interest, particularly because they are rich in targets for antibodies. Amongst them candidate biomarkers for early tumor diagnosis, prognosis and treatment have been detected. The suitability of several membrane-associated proteins as targets for drugs or antibodies has already been tested in preclinical and clinical studies. The results were encouraging in some cases, but not in all. They demonstrate that each type of tumor has its specific "Achilles heel", and that suitable targets of cancer diagnosis and therapy must be found for each kind of neoplasm. This implies that membrane-associated proteins for each type of tumor cell need to be investigated. This review describes the current technologies of membrane protein characterization in a first part and subsequently summarizes the membrane associated proteins currently being tested as targets for diagnosis and treatment in breast, prostate, thyroid, and colon cancer. Their function will be explained and their role in tumor biology will be discussed.

Thermography - a valuable tool to test hydrocephalus shunt patency.

INTRODUCTION: Shunt-function in hydrocephalic patients is verified by clinical examination and repeated cranial computed tomography (CCT) in most cases. Because of the disadvantages of multiple radiation especially in children it was our aim to introduce video-thermography as a simple and non-invasive methodology to evaluate shunt function. METHODS: 54 patients treated with shunts for hydrocephalus were tested. A ventriculo-peritoneal shunt had been implanted in 38 patients, a ventriculo-atrial shunt in 16 patients. Recent CCT-scans were available for all patients and served as control. None of the patients presented with clinical signs of shunt-dysfunction. The temperature of the skin covering the drainage catheter distal to the valve was recorded real-time by a calibrated infrared camera. After cooling the skin area downstream of the valve for exactly 1 min with an ice pack, changes of the skin temperature in the area downstream were registered by a thermocamera. The signals were transferred to a video screen and recorded on videotape. By off-line analysis of the obtained pseudo colour images variations of 0.1 degrees C in skin temperature could be measured. RESULTS: Temperature distribution of the area under investigation revealed a significant reduction of the skin temperature according to the location of the downstream catheter segment in 48 patients after cooling. In 6 patients skin temperature remained constant, although clinical evaluation and CCT-scan showed no signs of shunt dysfunction. Shunt patency could be verified in more than 85% of the patients by thermal imaging. CONCLUSION: Infrared-thermography is a valuable and promising tool for replacing CCT-scanning as a screening method to test shunt function in hydrocephalic patients.

Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression.

Osteopontin (OPN) was expressed in murine wild-type osteoclasts, localized to the basolateral, clear zone, and ruffled border membranes, and deposited in the resorption pits during bone resorption. The lack of OPN secretion into the resorption bay of avian osteoclasts may be a component of their functional resorption deficiency in vitro. Osteoclasts deficient in OPN were hypomotile and exhibited decreased capacity for bone resorption in vitro. OPN stimulated CD44 expression on the osteoclast surface, and CD44 was shown to be required for osteoclast motility and bone resorption. Exogenous addition of OPN to OPN-/- osteoclasts increased the surface expression of CD44, and it rescued osteoclast motility due to activation of the alpha(v)beta(3) integrin. Exogenous OPN only partially restored bone resorption because addition of OPN failed to produce OPN secretion into resorption bays as seen in wild-type osteoclasts. As expected with these in vitro findings of osteoclast dysfunction, a bone phenotype, heretofore unappreciated, was characterized in OPN-deficient mice. Delayed bone resorption in metaphyseal trabeculae and diminished eroded perimeters despite an increase in osteoclast number were observed in histomorphometric measurements of tibiae isolated from OPN-deficient mice. The histomorphometric findings correlated with an increase in bone rigidity and moment of inertia revealed by load-to-failure testing of femurs. These findings demonstrate the role of OPN in osteoclast function and the requirement for OPN as an osteoclast autocrine factor during bone remodeling.

Rapid quantitative bioassay of osteoinduction.

We developed a reproducible, relatively rapid bioassay that quantitatively correlates with the osteoinductive capacity of demineralized bone matrix obtained from human long bones. We have found that Saos human osteosarcoma cells proliferate in response to incubation with demineralized bone matrix and that an index of this proliferative activity correlates with demineralized bone matrix-induced osteogenesis in vivo. The bioassay (Saos cell proliferation) had an interassay coefficient of variation of 23 +/- 2% and an intra-assay coefficient of 11 +/- 1%. Cell proliferation was normalized to a standard sample of demineralized bone matrix with a clinically high osteoinductive capacity, which was assigned a value of one. The Saos cell proliferation for each sample was related to the standard and assigned a value placing it into the low (0.00-0.39), intermediate (0.40-0.69), or high (0.70-1.49) osteoinductive index group. Osteoinduction of human demineralized bone matrix was quantitated by expressing new bone formation as a function of the total bone volume (new bone plus the demineralized bone powder). The demineralized bone matrix was placed in pouches formed in the rectus abdominis muscles of athymic rats, and endochondral bone formation was assessed at 35 days following implantation, when marrow spaces in the ossicles were formed by new bone bridging the spaces between demineralized bone matrix particles. The proliferative index correlated with the area of new bone formation in histological sections of the newly formed ossicles. When the proliferative index (the osteoinductive index) was divided into low, intermediate, and high groups, the correlation between it and new bone formation (osteoinduction) was 0.850 (p < 0.0005) in 25 samples of demineralized bone matrix. There was no overlap in the osteoinduction stimulated between the samples with low and high osteoinductive indices. We conclude that the proliferation assay is useful for the routine screening of bone allograft donors for osteoinductive potential. Furthermore, the two-dimensional area of new bone formation, as it relates to total new bone area, is a quantitative measure of osteoinduction.

Abrogation of the alternative complement pathway by targeted deletion of murine factor B.

To investigate the role of complement protein factor B (Bf) and alternative pathway activity in vivo, and to test the hypothesized potential genetic lethal effect of Bf deficiency, the murine Bf gene was interrupted by exchange of exon 3 through exon 7 (including the factor D cleaving site) with the neor gene. Mice heterozygous for the targeted Bf allele were interbred, yielding Bf-deficient offspring after the F1 generation at a frequency suggesting that Bf deficiency alone has no major effect on fertility or fetal development. However, in the context of one or more genes derived from the 129 mouse strain, offspring homozygous for Bf deficiency were generated at less than expected numbers (P = 0.012). Bf-deficient mice showed no gross phenotypic difference from wild-type littermates. Sera from Bf-deficient mice lacked detectable alternative complement pathway activity; purified mouse Bf overcame the deficit. Classical pathway-dependent total hemolytic activity was lower in Bf-deficient than wild-type mice, possibly reflecting loss of the alternative pathway amplification loop. Lymphoid organ structure and IgG1 antibody response to a T-dependent antigen appeared normal in Bf-deficient mice. Sensitivity to lethal endotoxic shock was not significantly altered in Bf-deficient mice. Thus, deficiency of Bf and alternative complement activation pathway led to a less dramatic phenotype than expected. Nevertheless, these mice provide an excellent model for the assessment of the role of Bf and the alternative pathway in host defense and other functions in vivo.

Long-term effects on plasma lipids of diet and drugs to treat hypertension. Treatment of Mild Hypertension Study (TOMHS) Research Group.

OBJECTIVE: - To compare long-term plasma lipid changes among 6 antihypertensive treatment interventions for stage I (mild) hypertension. DESIGN: - Multicenter, randomized, double-blind, parallel-group clinical trial. SETTING: - Four academic clinical research units in the United States. PARTICIPANTS: - A total of 902 men and women, aged 45 to 69 years, with stage I diastolic hypertension (diastolic blood pressure <100 mm Hg), recruited from 11914 persons screened in their communities. INTERVENTIONS: - Participants were randomized to 1 of 6 treatment groups: (1) placebo, (2) beta-blocker (acebutolol), (3) calcium antagonist (amlodipine), (4) diuretic (chlorthalidone), (5) alpha1-antagonist (doxazosin), and (6) angiotensin-converting enzyme inhibitor (enalapril). All groups received intensive lifestyle counseling to achieve weight loss, dietary sodium and alcohol reduction, and increased physical activity. MAIN OUTCOME MEASURES: - Changes in plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides from baseline to annual visits through 4 years. RESULTS: - Mean changes in all plasma lipids were favorable in all groups. The degree of weight loss with fat-modified diet and exercise was significantly related to favorable lipid changes. Significant differences (P<.01) among groups for average changes during follow-up in each lipid were observed. Decreases in plasma total cholesterol and LDL cholesterol were greater with doxazosin and acebutolol (for plasma total cholesterol, 0.36 and 0.30 mmol/L [13.8 and 11.7 mg/dL], respectively), less with chlorthalidone and placebo (0.12 and 0.13 mmol/L [4.5 and 5.1 mg/dL], respectively). Decreases in triglycerides were greater with doxazosin and enalapril, least with acebutolol. Increases in HDL cholesterol were greater with enalapril and doxazosin, least with acebutolol. Significant relative increases in plasma total cholesterol with chlorthalidone compared with placebo at 12 months were no longer present at 24 months and beyond, when mean plasma total cholesterol for the chlorthalidone group fell below baseline. Analyses of participants continuing to receive chlorthalidone throughout the 4 years of follow-up indicated this was not due solely to an increasing percentage of participants changing or discontinuing use of medication during follow-up. CONCLUSIONS: - Weight loss with a fat-modified diet plus increased exercise produces favorable long-term effects on blood pressure and all plasma lipid fractions of adults with stage I hypertension; blood pressure reduction is enhanced to a similar degree by addition of a drug from any one of 5 classes of antihypertensive medication. These drugs differ quantitatively in influencing the degree of long-term favorable effects on blood lipids obtained with nutritional-hygienic treatment.

Alpha-blockade and thiazide treatment of hypertension. A double-blind randomized trail comparing doxazosin and hydrochlorothiazide.

This trial involved 107 patients in a two-group, parallel, double-blind, randomized study comparing the diuretic, hydrochlorothiazide (HCTZ) (dose 25 to 50 mg) and the alpha 1 antagonist, doxazosin (dose 2 to 16 mg). All randomized participants were followed for at least 1 year. Participants were recruited from the community. The study was carried out in four phases: Phase I-Baseline; Phase II-Monotherapy Titration; Phase III-Combination Therapy Titration; and Phase IV-Maintenance. The following measures were carried out: blood pressure, biochemistries, lipids/lipoproteins, quality of life, ambulatory electrocardiograms, echocardiograms, adverse experiences, and drug adherence. Both drugs were well tolerated, with only 4% taken off doxazosin and 7% off HCTZ. Adverse experiences were uncommon and mostly mild. Both drugs were effective in managing hypertension over 1 year of therapy. There was no difference noted in terms of efficacy of blood pressure lowering between the two study drugs, nor was there any evidence of tolerance developing or of any serious adverse effects. Average final doses for drugs were 7.8 mg for doxazosin and 36 mg for HCTZ. The results show that, over the course of 1 year, both drugs significantly lowered systolic and diastolic pressures compared to baseline; doxazosin (-19 and -16 mm Hg); HCTZ (-22 and 15 mm Hg). Blood pressure lowering was not significantly different between drugs. Sitting heart rate was not affected by drugs. Changes in quality of life measures were similar between groups. Echocardiographic measures at 1 year showed significant between-drug differences in change in left internal end systolic and diastolic dimensions and end systolic stress. Both doxazosin and HCTZ were effective drugs over 1 year for treating hypertension.

Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone.

Mice rendered deficient in IL-1 beta by gene targeting in embryonic stem cells develop and grow normally in a protected laboratory environment. Endotoxin-stimulated peritoneal macrophages from IL-1beta-deficient mice showed normal synthesis and cellular release of IL-1alpha after treatment with 5 mM ATP demonstrating that IL-1beta is not necessary for expression and release of the IL-1alpha isoform. Mice deficient in IL-1beta showed unaltered sensitivity to endotoxic shock, with or without pretreatment with D-galactosamine. In contrast, IL-1beta-deficient mice showed defective contact hypersensitivity responses to topically applied trinitrochlorobenzene (TNCB). This defect could be overcome either by application of very high doses of sensitizing antigen, or by local intradermal injection of recombinant IL-1beta immediately before antigen application. These data demonstrate an essential role for IL-1beta in contact hypersensitivity and suggest that IL-1beta acts early during the sensitization phase of response. They suggest an important role for IL-1beta in initiation of the host of response at the epidermal barrier.

Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2.

Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.

Once-daily monotherapy with trandolapril in the treatment of hypertension.

Once-daily antihypertensive drugs that control blood pressure (BP) for the full 24-h dosing period, enhance patient compliance and may reduce the cardiovascular complications of hypertension which occur with increased frequency in the early morning. Since some once-daily agents are more effective than others in maintaining antihypertensive effects toward the end of the 24-h dosing interval this study was designed to evaluate the duration of antihypertensive action of trandolapril using 48 h ambulatory blood pressure monitoring (ABPM) in 41 patients with mild-to-moderate essential hypertension. Twenty-four hour ABPM was performed on two consecutive days (48 h) after a 4 week single blind placebo run-in period and repeated after an 8 week double-blind period during which 20 patients were randomized to treatment with trandolapril (2-4 mg once-daily) and 21 patients to matching placebo. During the second 48 h monitoring period, placebo rather than active medication was taken by both of the groups at the beginning of the second 24 h segment. Trandolapril reduced ambulatory systolic and diastolic BP by 9.4 and 6.2 mm Hg respectively (P < or = 0.01) during the first 24 h of the post treatment monitoring period while placebo increased the systolic and diastolic BPs in the same period by 3.8 and 2.6 mm Hg (P < 0.05). During the second monitoring period (hours 25-48), trandolapril reduced systolic and diastolic BP by 5.6 and 3.9 mm Hg while placebo increased BP by 2.3 and 1.6 mm Hg (P < 0.03). When compared to placebo by 2 h time blocks, throughout the 2 days of monitoring, trandolapril produced clinically significant decreases in systolic and diastolic BP for 30 and 28 h following dosing. This indicates that trandolapril can be considered a true once-daily antihypertensive agent.

Effectiveness of short-course therapy (5 days) with cefuroxime axetil in treatment of secondary bacterial infections of acute bronchitis.

Five hundred thirty-seven patients were enrolled in two independent, investigator-blinded, multicenter, randomized clinical trials comparing the clinical and bacteriologic efficacies and the safety of 5- or 10-day treatment with cefuroxime axetil with those of 10-day treatment with amoxicillin-clavulanate in the treatment of secondary bacterial infections of acute bronchitis. Patients received either 5 or 10 days of treatment (n = 177 in each group) with cefuroxime axetil at 250 mg twice daily or 10 days of treatment (n = 183) with amoxicillin-clavulanate at 500 mg three times daily. Patients in the cefuroxime axetil (5 days) group received placebo on days 6 to 10. Bacteriologic assessments were based on sputum specimen cultures obtained preceding and, when possible, following treatment. Organisms were isolated from the pretreatment sputum specimens of 242 of 537 (45%) patients, with the primary pathogens being Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus (28, 25, 13, 9, and 8% of isolates, respectively). Pathogens were eradicated or presumed to be eradicated in 87% (52 of 60), 91% (53 of 58), and 86% (60 of 70) of bacteriologically evaluable patients treated with cefuroxime axetil (5 days), cefuroxime axetil (10 days), and amoxicillin-clavulanate, respectively. A satisfactory clinical outcome (cure or improvement) was achieved in 82% (107 of 130), 86% (117 of 136), and 83% (130 of 157) of the clinically evaluable patients treated with cefuroxime axetil (5 days), cefuroxime axetil (10 days), and amoxicillin-clavulanate, respectively. Treatment with amoxicillin-clavulanate was associated with a significantly higher incidence of drug-related adverse events than was treatment with cefuroxime axetil for either 5 or 10 days (P = 0.001), primarily reflecting a higher incidence of drug-related gastrointestinal adverse events (37 versus 19 and 15%, respectively; P < 0.001), particularly diarrhea and nausea. These results indicate that treatment with cefuroxime axetil at 250 mg twice daily for 5 days is as effective as treatment for 10 days with either the same dose of cefuroxime axetil or amoxicillin-clavulanate at 500 mg three times daily in patients with acute bronchitis. In addition, treatment with cefuroxime axetil for either 5 or 10 days is associated with significantly fewer gastrointestinal adverse events, particularly diarrhea and nausea, than is 10-day treatment with amoxicillin-clavulanate.

Clinical comparison of cefuroxime axetil and amoxicillin/clavulanate in the treatment of patients with secondary bacterial infections of acute bronchitis.

Two independent, investigator-blinded, multicenter, randomized clinical trials compared the clinical and bacteriologic efficacy and safety of two oral antibiotics, cefuroxime axetil and amoxicillin/clavulanate, in the treatment of patients with secondary bacterial infections of acute bronchitis (hereafter denoted acute bronchitis). Three hundred sixty patients with signs and symptoms of acute bronchitis were enrolled at 22 centers and were randomly assigned to receive 10 days of treatment with either cefuroxime axetil 250 mg twice daily (BID) (n= 177) or amoxicillin/clavulanate 500 mg three times daily (TID) (n = 183). Patients were assessed for both clinical and bacteriologic responses once during treatment (at 3 to 5 days) and twice after treatment (at 1 to 3 days and at 13 to 15 days). Bacteriologic assessments were based on sputum specimen cultures obtained before treatment and, when possible, after treatment. Organisms were isolated from the pretreatment sputum specimens of 162 (45%) of 360 patients, with the primary pathogens being Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus (28%, 25%, 11%, 9%, and 8% of isolates, respectively). Thirty-four percent of the H influenzae isolates and 94% of the M catarrhalis isolates that were tested for beta-lactamase production were positive. A satisfactory clinical outcome (cure or improvement) was achieved in 86% (117 of 136) and 83% (130 of 157) of the clinically assessable patients treated with cefuroxime axetil or amoxicillin/clavulanate, respectively (P = 0.45). With respect to the eradication of bacterial pathogens, a satisfactory outcome (cure, presumed care, or cure with colonization) was obtained in 91% (53 of 58) and 86% (60 of 70) of bacteriologically assessable patients treated with cefuroxime axetil or amoxicillin/clavulanate, respectively (P = 0.32). Treatment with amoxicillin/clavulanate was associated with a significantly higher incidence of drug-related adverse events than was treatment with cefuroxime axetil (39% vs 23%; P = 0.001), primarily reflecting a higher incidence of drug-related gastrointestinal adverse events (37% vs 15%; P < 0.001), particularly diarrhea and nausea. Four patients in the cefuroxime axetil group and eight patients in the amoxicillin/clavulanate group withdrew from the study because of drug-related adverse events. These results indicate that cefuroxime axetil 250 mg BID is as effective as amoxicillin/clavulanate 500 mg TID in the treatment of patients with acute bronchitis but produces fewer gastrointestinal adverse events, particularly diarrhea and nausea.

Losartan with hydrochlorothiazide in the treatment of hypertension.

AIM: To review the efficacy and safety of losartan and hydrochlorothiazide compared to losartan alone, hydrochlorothiazide alone or placebo in the treatment of mild to moderate hypertension in a clinical trial. PATIENTS AND METHODS: A randomly allocated, placebo-controlled, double-blind parallel study was performed in 40 clinical centers throughout the United States. A total of 703 males and females aged 18-75 years with a sitting diastolic blood pressure of 95-115 mmHg entered the trial and 604 completed the 12-week protocol. The participants were randomly assigned to concomitant therapy once a day with: (1) 50 mg losartan and 6.25 mg hydrochlorothiazide, (2) 50 mg losartan and 12.5 mg hydrochlorothiazide, (3) 50 mg losartan alone, (4) 12.5 mg hydrochlorothiazide alone or (5) placebo. All participants were followed for 12 weeks. RESULTS: At baseline, mean trough sitting diastolic blood pressure was 100.9-101.7 mmHg, with no significant difference between treatment groups. Sitting diastolic blood pressure fell 4.0 mmHg with placebo, 7.2 mmHg with 12.5 mg hydrochlorothiazide, 7.2 mmHg with 50 mg losartan, 9.3 mmHg with 50 mg losartan + 6.25 mg hydrochlorothiazide, and 13.2 mmHg with 50 mg losartan + 12.5 mg hydrochlorothiazide. The fall in mean trough sitting systolic blood pressure was 2.4, 9.3, 10.7, 12.0 and 17.9 mmHg for the respective groups. After subtracting the placebo effect, the reductions in blood pressure induced by losartan and hydrochlorothiazide were additive for both sitting diastolic and systolic blood pressures and approximately equaled the reduction seen with the combination of losartan and hydrochlorothiazide. There were no significant differences in adverse events between treatment groups. CONCLUSIONS: The concomitant administration of 50 mg losartan + 12.5 mg hydrochlorothiazide produced additive falls in sitting diastolic and systolic blood pressures which were greater than that achieved with either drug alone. On the basis of the adverse effects reported, the combination was well tolerated.

Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions in mild hypertension.

Renal effects of mild hypertension and therapy have not been established. Since urinary albumin and N-acetyl-beta-D-glucosaminidase excretions reflect renal effects of hypertension, they were related to blood pressure, other cardiovascular risk factors, cardiac target organ effects, and response to therapy in mild hypertension (diastolic blood pressure 85-99 mm Hg). Participants were from two clinics of the Treatment of Mild Hypertension Study (TOMHS), a multicenter randomized, double-blind, controlled trial. Participants received nutritional-hygienic therapy and one of five active drugs or placebo. Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions were assessed prospectively using office "spot" collections from one clinic (n = 213) and retrospectively using overnight collections from the other clinic (n = 210). Relationships were determined between protein excretions and blood pressure, age, gender, race, blood glucose, cholesterol concentrations, and indices of body mass and left ventricular mass and function at baseline. Treatment effects were assessed after 3 to 12 months. Spot and overnight albumin excretions related positively to baseline systolic blood pressure by univariate analyses. Spot albumin excretion related positively to systolic blood pressure, age, creatinine clearance, and left ventricular function while overnight albumin excretion related positively to left ventricular mass and female gender by multiple regression analyses. Spot, but not overnight, albumin excretion declined significantly with active drug therapy. N-acetyl-beta-D-glucosaminidase excretion did not relate to blood pressure or decline with therapy. The combined results suggest albumin excretion correlates with blood pressure, decreases with antihypertensive drug therapy, and is associated with greater left ventricular function and mass, as well as glomerular filtration rate, even at mild levels of hypertension.

Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin.

Mice rendered deficient in lymphotoxin (LT) by gene targeting in embryonic stem cells have no morphologically detectable lymph nodes or Peyer's patches, although development of the thymus appears normal. Within the white pulp of the spleen, there is failure of normal segregation of B and T cells. Spleen and peripheral blood contain CD4+CD8- and CD4-CD8+ T cells in a normal ratio, and both T cells subsets have an apparently normal lytic function. Lymphocytes positive for immunoglobulin M are present in increased numbers in both the spleen and peripheral blood. These data suggest an essential role for LT in the normal development of peripheral lymphoid organs.

Induction of peri-insulitis but not diabetes in islet transplants expressing a single foreign antigen. A multi-stage model of disease.

We have created a new transgenic model in which the human Epstein-Barr virus receptor, CR2 (CD21), has been expressed in pancreatic beta-cells. Mice derived from three transgenic founders bred into H-2b (C57BL/6) or H-2k (CBA) genetic backgrounds did not become spontaneously diabetic. After transplantation of CR2-expressing islets under the kidney capsule of genetically matched recipients, a histologic picture of peri-insulitis was found. However, animals did not manifest cellular invasion of the islets, destruction of the islets, or diabetes for at least 230 days. Significant numbers of both T and B lymphocytes were found in the cell population surrounding the islets. A pronounced serologic response to CR2 was also present and appeared to precede the onset of peri-insulitis. Thus, in this model, we have separated the process of diabetes induction into at least two phases. One is associated with peri-islet infiltration and an antibody response. However, at least one second signal is likely necessary for the process of islet destruction to follow.

Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group.

OBJECTIVE: To compare six antihypertensive interventions for the treatment of mild hypertension. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Four hypertension screening and treatment centers in the United States. PARTICIPANTS: Hypertensive men and women, aged 45 to 69 years, with diastolic blood pressure less than 100 mm Hg. INTERVENTION: Sustained nutritional-hygienic advice to all participants to reduce weight, dietary sodium intake, and alcohol intake, and increase physical activity. Participants were randomly allocated to take (1) placebo (n = 234); (2) chlorthalidone (n = 136); (3) acebutolol (n = 132); (4) doxazosin mesylate (n = 134); (5) amlodipine maleate (n = 131); or (6) enalapril maleate (n = 135). MAIN OUTCOME MEASURES: Blood pressure, quality of life, side effects, blood lipid levels and analysis of other serum components, echocardiographic and electrocardiographic changes, and incidence of cardiovascular events over an average of 4.4 years of follow-up. RESULTS: Blood pressure reductions were sizable in all six groups, and were significantly greater for participants assigned to drug treatment than placebo (-15.9 vs -9.1 mm Hg for systolic blood pressure and -12.3 vs -8.6 mm Hg for diastolic blood pressure; P < .0001). After 4 years, 59% of participants assigned to placebo and 72% of participants given drug treatment continued on their initial medication as monotherapy. A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group (5.1% vs 7.3%; P = .21). After including other clinical events, the percentage of participants affected was 11.1% for those in the drug-treatment groups and 16.2% for those in the placebo group (P = .03). Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group. Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass, blood lipid levels, and other outcome measures. CONCLUSIONS: As an initial regimen, drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone. Drug-treatment group differences were minimal. Pending results from large-scale clinical trials to evaluate drug treatments for their effect on cardiovascular clinical events, these findings support the recommendations of the new fifth Joint National Committee report regarding treatment choices for people with stage 1 ("mild") hypertension.