Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 microg/ml. A CSF maximum (CmaxCSF) of 0.63 +/- 0.50 microg/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t1/2beta] of 7.36 +/- 2.89 h in CSF versus t1/2beta of 1.69 +/- 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other beta-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

Human immunodeficiency virus infection, Part II

The acceptance of highly active antiretroviral therapy (HAART) among patients and health care providers has had a dramatic impact on the epidemiology and clinical characteristics of many opportunistic infections associated with human immunodeficiency virus (HIV). Previously intractable opportunistic infections and syndromes are now far less common. In addition, effective antibiotic prophylactic therapies have had a profound impact on the risk of patients developing particular infections and on the incidence of these infections overall. Most notable among these are Pneumocystis carinii, disseminated Mycobacterium avium complex, tuberculosis, and toxoplasmosis. Nevertheless, infections continue to cause significant morbidity and mortality among patients who are infected with HIV. The role of HAART in many clinical situations is unquestioned. Compelling data from clinical trials support the use of these therapies during pregnancy to prevent perinatal transmission of HIV. HAART is also recommended for health care workers who have had a "significant" exposure to the blood of an HIV-infected patient. Both of these situations are discussed in detail in this article. In addition, although more controversial, increasing evidence supports the use of HAART during the acute HIV seroconversion syndrome. An "immune reconstitution syndrome" has been newly described for patients in the early phases of treatment with HAART who develop tuberculosis, M avium complex, and cytomegalovirus disease. Accumulating data support the use of hydroxyurea, an agent with a long history in the field of myeloproliferative disorders, for the treatment of HIV. Newer agents, particularly abacavir and adefovir dipivoxil, are available through expanded access protocols, and their roles are being defined and clarified.     

NIDA technical review: nitrite inhalants

Nitrite inhalants are commonly abused substances in the US and Europe. "Nitrite inhalants and AIDS" was a popular topic in the early 1980s when the cause of AIDS was not known. With the discovery of HIV, concern about nitrite use wained. However, nitrite inhalant use is associated with behavioral relapse and HIV transmission among gay men, with decreased lymphocyte counts and natural killer cell activity in laboratory studies, and remains a candidate "cofactor" in the pathogenesis of AIDS-related Karposi sarcoma. Discouraging nitrite use continues to be a worthwhile public health goal. Participants recommend specific research efforts.     

Reduction of disulfide bonds in an amyloidogenic Bence Jones protein leads to formation of "amyloid-like" fibrils in vitro

Motivated by the finding that the amino acid sequence of the Bence Jones protein BJP-DIA was identical to that of the main protein component of the amyloid fibrils obtained from the same patient with AL-amyloidosis, (Klafki, H.-W., Kratzin, H.-D., Pick, A.-I., Eckart, K., Karas, M. & Hilschmann, N. (1992) Biochemistry 31, 3265-3272.), we attempted to create "amyloid-like" fibrils from the Bence Jones protein in vitro, without addition of proteolytic enzymes. Reduction of BJP-DIA, solubilized in PBS, pH 7.4, overnight at 37 degrees C resulted in the formation of a precipitate which had affinity for the dye Congo red. Electron microscopy of negatively stained samples of the reduced protein revealed aggregates of linear unbranched fibrils. SDS-polyacrylamide gel electrophoresis demonstrated that the precipitate consisted almost exclusively of intact light chain molecules. This result makes it possible to deduce a molecular model of these amyloid fibrils generated in vitro.     

Definition of inseparably fused ventricular myocardium in thoracopagus: fetal echocardiographic utility and pathologic refinement

Correlative echocardiographic and pathological findings in a thoracopagus with conjoined hearts are reported. One twin had tricuspid atresia with discordant atrioventricular connections and concordant ventriculoarterial connections. The morphologic right ventricle was hypoplastic and there was a large muscular ventricular septal defect. The other twin had hypoplasia of the mitral valve anulus and left ventricle with double-outlet right ventricle and pulmonary valve atresia. The tricuspid valve was severely insufficient in part because of a large orifice and redundant, elongated leaflets with abnormal chordal attachments. The left ventricles of these two twins shared a perforated common "free wall" with at least two large defects allowing mixing of the circulations at that level. Not all anatomic details were established conclusively by fetal echocardiography; however, sufficient diagnostic information was obtained to support a decision not to aggressively resuscitate these twins after elective cesarean delivery at 31 weeks' gestation.     

MVA-vaccine in primovaccination against smallpox after the age of three (author's transl)

These are the results of 417 primary vaccinations against smallpox with MVA, an attenuated vaccine. All of the patients were over three years old. In Europe, this group has an increased risk of postvaccinal encephalitis. The intracutaneous inoculation produced a light local infiltration and only 11.7% showed a light generalized reaction. In order to attain a reliable immunity, a second inoculation was performed one week later, epicutaneously with Elstree-vaccine. The local reaction was in general that of a normal revaccination, and 79.4% of our patients had neither fever nor general symptoms. Among the others no one became seriously ill. We did not observe any complications specific for a smallpox vaccination. In comparison to the other vaccination methods currently used, the MVA "Two-step"-vaccination is probably the safest. Its risk of a postvaccinal encephalitis is supposed to be lower according to animal experiments and theoretical considerations. This hypothesis has been confirmed meanwhile by the results of several thousand vaccinations in the already mentioned age-group.     

LPS tolerance in monocytes/macrophages: three 3' cytosins are required in the DNA binding motif for detection of upregulated NF-kappa B p50 homodimers

When monocytes are stimulated with LPS (lipopolysaccharide) repeatedly then the initially high expression of the TNF (tumor necrosis factor) gene is only very low, i.e. the cells are tolerant to LPS. Tolerant cells still express the CD14 receptor and they can still be activated to mobilize NF-kappa B into nucleus. Analysis of the binding proteins employing the -605 motif of the human TNF promoter (GGGGCTGTCCC) revealed that in tolerant cells of the human monocytic cell line Mono Mac 6 there is a predominance of p50p50 of NF-kappa B. We now show that a mutant motif that exchanges the terminal 3' C for a G fails to bind the p50 homodimer that is upregulated in LPS toler ant human Mono Mac 6 cells. The same is true for nuclear extracts taken from the murine P388D1 macrophage cell line when tested with the -516 motif of the murine TNF promoter (GGGGGCTTTCCC). Here the wild type motif gives efficient binding of p50p50 that again is upregulated in tolerant cells whereas a mutant with a 3' G shows hardly any binding of p50p50. Conversely, the murine kappa light chain enhancer motif (GGGGACTTTCCG) does not efficiently bind the nuclear p50p50 from tolerant murine P388 macrophages. Binding is, however, readily detected when the 3' G is replaced by a C. These data show that the detection of upregulated p50 homodimers in LPS tolerant cells is dependent on subtle differences in the sequence of the DNA binding motif.     

Measurements and correlations for gas liquid surface tension at high pressure and high temperature

Surface tension of water/nitrogen and water–phenol/nitrogen systems was successfully measured by the hanging drop method in a wide domain of temperature (from 100 to 300°C) and pressure (from 4 to 30MPa), conditions little explored in litterature. Results show that surface tension of water–phenol mixtures decreases as phenol mass fraction increases. This decrease is observed under saturated and unsaturated conditions and is more pronounced at low temperatures and does not seem to depend on pressure. The effect of saturation on surface tension in the water/nitrogen system has been correlated with water vapor pressure by using experimental points with a great accuracy. For the water–phenol/nitrogen system, experimental data obtained with different mass fraction of phenol were correlated using Macleod‐Sugden equation for mixtures. © 2018 American Institute of Chemical Engineers © 2018 American Institute of Chemical Engineers AIChE J, 64: 4110–4117, 2018