Morphometric evidence for a striking B-cell reduction at the clinical onset of type 1 diabetes

Summary The distribution and volume of the pancreatic endocrine cells were studied in a case of type 1 diabetes with a duration of approximately 7 days. Immunocytochemical techniques combined with morphometry were used. The PP-cell rich lobe, making up about 10% of the total pancreatic volume, was not included in this study. The volume density and the absolute volume of the B-cells was found to be reduced to about one third to one seventh of the values determined in four controls of similar age and/or pancreatic volume. The A-cell volume was also diminished whereas the D- and PP-cell volume remained constant. As B-cell necroses could not be detected and insulitis was in the initial stages of development it is concluded that the destruction of B-cells proceeds slowly in type 1 diabetes. In the majority of cases it probably starts years before the clinical onset of the disease.Dedicated to Prof. Dr. J. Kracht in honour of his sixtieth birthdayPresented in part at the eighteenth annual EASD meeting in Budapest 1982Supported by Deutsche Forschungsgemeinschaft, SFB 34, Hamburg     

Increased intracellular free calcium and sensitivity to angiotensin II in platelets of preeclamptic women

Preeclampsia is characterized by a generalized vasoconstriction and increased vascular sensitivity to angiotensin II. Intracellular free calcium, implicated in vascular smooth muscle contraction, has been found to be elevated in platelets of other hypertensive disorders. We therefore measured intracellular free calcium concentrations by using the fluorescent probe quin-2 in platelets of six patients with preeclampsia and compared them to measurements in ten normotensive pregnant women and ten age-matched nonpregnant women. Intracellular free calcium was also determined in the preeclamptic women after delivery. We found that intracellular free calcium was slightly elevated in normal pregnancy (102 +/- 13 nmol/L v 87 +/- 17 nmol/L) but was markedly increased in preeclampsia (138 +/- 13 nmol/L, P less than .05). This increase disappeared six weeks after delivery (84 + 10 nmol/L, P less than .01). To investigate whether the increased intracellular free calcium was related to angiotensin II, the platelets were exposed to thrombin and angiotensin II in vitro. Exposure to thrombin and angiotensin II caused a dose-dependent increase in intracellular free calcium. The intracellular response to thrombin was not significantly different in the three groups. However, stimulation with angiotensin II revealed an increased response in intracellular free calcium in preeclampsia (P less than .05) that disappeared after delivery. Our findings show a sustained increase in platelet intracellular free calcium in preeclampsia and suggest a functional alteration of the angiotensin II receptor in this disease.     

Impact of viral E2-gene status on outcome after radiotherapy for patients with human papillomavirus 16-positive cancer of the uterine cervix

PURPOSE: Integration of high-risk papillomavirus DNA has been considered an important step in oncogenic progression to cervical carcinoma. Disruption of the human papillomavirus (HPV) genome within the E2 gene is frequently a consequence. This study investigated the influence of episomal viral DNA on outcome in patients with advanced cervical cancer treated with primary radiotherapy. METHODS AND MATERIALS: Paraffin-embedded biopsies of 82 women with locally advanced cervical cancer could be analyzed for HPV infection by multiplex polymerase chain reaction (PCR) by use of SPF1/2 primers. E2-gene intactness of HPV-16-positive samples was analyzed in 3 separate amplification reactions by use of the E2A, E2B, E2C primers. Statistical analyses (Kaplan-Meier method; log-rank test) were performed for overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS), and distant metastases-free survival (DMFS). RESULTS: Sixty-one (75%) of 82 carcinomas were HPV positive, 44 of them for HPV-16 (72%). Seventeen of the 44 HPV-16-positive tumors (39%) had an intact E2 gene. Patients with a HPV-16-positive tumor and an intact E2 gene showed a trend for a better DFS (58% vs. 38%, p = 0.06) compared with those with a disrupted E2 gene. A nonsignificant difference occurred regarding OS (87% vs. 66%, p = 0.16) and DMFS (57% vs. 48%, p = 0.15). CONCLUSION: E2-gene status may be a promising new target, but more studies are required to elucidate the effect of the viral E2 gene on outcome after radiotherapy in HPV-positive tumors.     

Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections

The present study evaluated cellular and humoral immune parameters in myeloma patients, focusing on the effect of treatment and the risk of opportunistic infections. Peripheral blood lymphocyte subsets and serum levels of nonmyeloma immunoglobulins (Ig) were analysed in 480 blood samples from 77 myeloma patients. Untreated myeloma patients exhibited significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells, as well as nonmyeloma IgA, IgG and IgM. Conventional-dose chemotherapy resulted in significantly reduced CD4+ and even further decline of CD4+/CD45RO+ and CD19+ cells, most notably in relapsed patients. Additional thalidomide treatment had no significant effects on these parameters. Following high-dose chemotherapy (HD-CTX), prolonged immunosuppression was observed. Although CD8+, NK, CD19+ and CD+/CD45RO+ cells recovered to normal values within 60, 90, 360 and 720 days, respectively, CD4+ counts remained reduced even thereafter. Nine opportunistic infections were observed, including five cytomegalovirus (CMV) diseases, one Pneumocystis carinii pneumonia (PCP) and three varicella zoster virus infections with CMV diseases and PCP occurring exclusively after HD-CTX. Opportunistic infections were correlated with severely reduced CD4+, as well as CD4+/CD45RO+ and CD19+ counts. Thus, myeloma patients display cellular and humoral immunodeficiencies, which increase following conventional as well as HD-CTX, and constitute an important predisposing factor for opportunistic infections.     

Recent developments in antibacterial drug discovery: microbe-derived natural products--from collection to the clinic

The pharmaceutical industry has historically relied on nature to provide compounds for antibacterial drug discovery. In recent years, several pharmaceutical companies have scaled back their efforts in natural product research. Nevertheless, the screening of natural products for antibacterial activity continues to provide excellent sources of biologically and chemically informative leads for new drugs. New technologies in high-throughput cultivation, genetic approaches to biodiversity and discovery of relatively untapped sources of natural products are expanding the ability to find novel, potent and highly selective antibacterial structures. Advances in purification, dereplication and structure elucidation, combined with the ability to chemically or biologically derivatise hits, aim to make the timeline for natural product-derived drug discovery similar or shorter than that expected for small synthetic molecules. This review addresses the strengths and shortcomings of technologies focused on microbe-derived natural products for antibacterial drug discovery and stresses the need for commitment to these approaches in order to achieve the goal of delivering safe, efficacious and high-quality medicines in the long run.