ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling.

RATIONALE: Pressure overload induces adaptive remodeling processes in the heart. However, when pressure overload persists, adaptive changes turn into maladaptive alterations leading to cardiac hypertrophy and heart failure. ATF3 is a stress inducible transcription factor that is transiently expressed following neuroendocrine stimulation. However, its role in chronic pressure overload dependent cardiac hypertrophy is currently unknown. OBJECTIVE: The objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes. METHODS AND RESULTS: Pressure overload was induced by phenylephrine (PE) mini-osmotic pumps in various mice models of whole body, cardiac specific, bone marrow (BM) specific and macrophage specific ATF3 ablations. We show that ATF3-KO mice exhibit a significantly reduced expression of cardiac remodeling markers following chronic pressure overload. Consistently, the lack of ATF3 specifically in either cardiomyocytes or BM derived cells blunts the hypertrophic response to PE infusion. A unique cross-talk between cardiomyocytes and macrophages was identified. Cardiomyocytes induce an ATF3 dependent induction of an inflammatory response leading to macrophage recruitment to the heart. Adoptive transfer of wild type macrophages, but not ATF3-KO derived macrophages, into wild type mice potentiates maladaptive response to PE infusion. CONCLUSIONS: Collectively, this study places ATF3 as a key regulator in promoting pressure overload induced cardiac hypertrophy through a cross-talk between cardiomyocytes and macrophages. Inhibiting this cross-talk may serve as a useful approach to blunt maladaptive remodeling processes in the heart.

Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies.

In addition to its direct effects on tumor cells, chemotherapy can rapidly activate various host processes that contribute to therapy resistance and tumor regrowth. The host response to chemotherapy consists of changes in numerous cell types and cytokines. Examples include the acute mobilization and tumor homing of pro-angiogenic bone marrow-derived cells, activation of cells in the tumor microenvironment to produce systemic or paracrine factors, and tissue-specific responses that provide a protective niche for tumor cells. All of these factors reduce chemotherapy efficacy, and blocking the host response at various levels may therefore significantly improve treatment outcome. However, before the combination of conventional chemotherapy with agents blocking specific aspects of the host response can be implemented into clinical practice, a better understanding of the molecular mechanisms behind the host response is required.

Copper binding to the PrP isoforms: a putative marker of their conformation and function.

We show here that PrP(C), the normal isoform of the prion protein (PrP(Sc)), could be retained by a Cu(2+)-loaded resin through two different binding sites. Contrarily, PrP(Sc) was not retained at all by such resin. This constitutes a new prion-specific property of PrP(Sc), which in addition to protease resistance and beta-sheet content, may result from its aberrant conformation.

A protease-resistant prion protein isoform is present in urine of animals and humans affected with prion diseases.

Prion protein (PrP)(Sc), the only known component of the prion, is present mostly in the brains of animals and humans affected with prion diseases. We now show that a protease-resistant PrP isoform can also be detected in the urine of hamsters, cattle, and humans suffering from transmissible spongiform encephalopathies. Most important, this PrP isoform (UPrP(Sc)) was also found in the urine of hamsters inoculated with prions long before the appearance of clinical signs. Interestingly, intracerebrally inoculation of hamsters with UPrP(Sc) did not cause clinical signs of prion disease even after 270 days, suggesting it differs in its pathogenic properties from brain PrP(Sc). We propose that the detection of UPrP(Sc) can be used to diagnose humans and animals incubating prion diseases, as well as to increase our understanding on the metabolism of PrP(Sc) in vivo.

A C-terminal-truncated PrP isoform is present in mature sperm.

PrP(C), the normal isoform of the prion component PrP(Sc), is a 33-35-kDa glycophosphatidylinositol-anchored glycoprotein expressed in the plasma membrane of many cells and especially in the brain. The specific role of PrP(C) is unknown, although lately it has been shown to bind copper specifically. We show here that PrP(C) is present even in mature sperm cells, a polarized cell that retains only the minimal components required for DNA delivery, movement, and energy production. As opposed to PrP(C) in other cells, PrP in ejaculated sperm cells was truncated in its C terminus in the vicinity of residue 200. Sperm PrP, although membrane-bound, was not released by phosphatidylinositol phospholipase C as well as not localized in cholesterol-rich microdomains (rafts). Although no infertility was reported for PrP-ablated mice in normal situations, our results suggest that sperm cells originating from PrP-ablated mice were significantly more susceptible to high copper concentrations than sperm from wild type mice, allocating a protective role for PrP in specific stress situations related to copper toxicity. Since the functions performed by proteins in sperm cells are limited, these cells may constitute an ideal system to elucidate the function of PrP(C).

Immediate immunosuppression caused by acute HIV-1 infection: a fulminant multisystemic disease 2 days post infection.

A healthy 19-year-old woman had vaginal intercourse on a single occasion with an HIV-1 positive male from Gambia. Two days later she developed an acute HIV infection presenting as a fulminant multisystem disease that lasted for 35 hospital days and included: immediate immunosuppression with extreme CD4+ lymphocytopenia and combined with CD8+ lymphocytosis, neutropenia and hypogammaglobulinemia; intermittent spiking fever; pneumonitis; hepatitis; changing skin rashes; peripheral neuropathy with myopathy, and panencephalitis. P24 antigen was detected by Western blot on day 23 and seroconversion was detected by ELISA on day 25. Cultured lymphocytes from peripheral blood and cerebrospinal fluid grew HIV-1.

Involvement of the kidneys in Mediterranean spotted fever and murine typhus.

We reviewed 58 patients, 27 with murine typhus (MT) and 31 with Israeli Mediterranean spotted fever (IMSF), hospitalized at the Sheba Medical Center 1979-1988. Five patients with MT and five with IMSF had evidence of renal impairment. One patient with MT underwent a renal biopsy, and two patients with IMSF died and had autopsy examinations with histology of the kidney. The principal histopathological lesion found in those most severe cases of rickettsiosis-induced renal failure was multifocal perivascular interstitial nephritis. In contrast with previous reports, involvement of the kidneys in rickettsial infection seems to be relatively common. Early diagnosis and treatment with hydration and specific antimicrobial agents is mandatory to prevent morbidity.

Hyporeninemic hypoaldosteronism associated with multiple myeloma: 11 years of follow-up.

Hyporeninemic hypoaldosteronism is an important underlying condition, causing hyperkalemia with hyperchloremic metabolic acidosis, disproportionate to the degree of renal insufficiency present. The principal defect in this syndrome is a reduced level of plasma renin activity, which results in secondary hypoaldosteronism. Diabetes mellitus is usually the primary underlying renal disease, though other causes of renal diseases associated with this syndrome have been described. This case report describes for the first time an elderly patient with multiple myeloma, in remission for more than 11 years, associated with the syndrome of hyporeninemic hypoaldosteronism at the time of diagnosis. The complete resolution of the syndrome after vigorous chemotherapy is an intriguing possibility.

Leptospirosis in pregnancy and its effect on the fetus: case report and review.

We report the case of a pregnant woman with leptospirosis who gave birth to a healthy baby. We also review 15 previously reported cases of leptospirosis in pregnancy. Of these 15 cases, eight women had abortions, two delivered healthy babies, and four delivered babies who had signs of active leptospirosis; in one case, the fate of the fetus was not stated. It appears that women are more likely to spontaneously abort if leptospirosis occurs in the early months of pregnancy. Since congenital infection is rare, leptospirosis should not necessarily be considered an indication to terminate pregnancy. Increased awareness of the possibility of leptospirosis for pregnant women who live in areas where the disease is endemic is of utmost importance for early detection and treatment of the disease and, thus, for the safety of the fetus.

Rickettsial infection of the central nervous system: the role of prompt antimicrobial therapy.

Rickettsial diseases of man, which are prevalent in all the continents (except Antartica) continue to be a major health problem in tropical and temperate parts of the world. Rickettsioses must be considered in every traveller seeking medical attention soon after returning from endemic areas, since the disease can be associated with significant morbidity. When a definite diagnosis has been made by specific serological tests, prompt antimicrobial therapy is indicated. A tetracycline should be regarded as the drug of choice due to its high efficacy, low toxicity, superior in vitro activity and the possibility of relapse which can follow chloramphenicol therapy.

Long-term follow-up after leptospirosis.

Human leptospirosis is an infectious disease that is a substantial problem in the Third World, but it can occur in developed countries as well. Survivors of the acute disease are considered to recover without sequelae, though little literature exists on long-term follow-up among these patients. Eleven patients, at an average of 22 years after acute leptospirosis, were reevaluated for possible delayed sequelae. Results showed that liver and renal disease had resolved, but headache and ophthalmic sequelae persisted. Even though the number of patients involved in this study is small, it appears that the eyes, particularly the anterior chambers, may be the site of continuing morbidity after acute human leptospirosis. The pathogenesis for persistent headache is not known.

Q fever meningoencephalitis associated with bilateral abducens nerve paralysis, bilateral optic neuritis and abnormal cerebrospinal fluid findings.

Q fever is an zoonosis caused by Coxiella burnetti, the clinical features of which are often nonspecific and self-limited. Involvement of the central nervous system is rare and is usually seen as a complication of endocarditis caused by this rickettsial organism in the chronic disease. Specific neurological manifestations in the course of the acute illness aseptic meningitis, encephalitis, toxic confusional states, extrapyramidal signs, dementia and behavioral disturbances. We describe a patient who developed reversible bilateral abducens nerve paralysis and bilateral optic neuritis in the course of acute Q fever meningoencephalitis.

Drug-induced post-surgical haemorrhage resulting from trimethoprim-sulphamethoxazole. A case report.

A case of life-endangering post-operative haemorrhage due to thrombocytopenia resulting from administration of trimethoprim-sulphamethoxazole is described. Withdrawal of the drug led to complete recovery. This side effect should be kept in mind, especially in patients scheduled for surgical intervention. As thrombocytopenia may develop insidiously and gradually, it is highly recommended to perform full blood tests immediately prior to surgery and repeat them in the post-operative period.

Delayed neurologic display in murine typhus. Report of two cases.

Two cases of murine typhus with prolonged neurologic manifestations appearing after the febrile stage of the illness are described. One patient had behavioral and memory disturbances for almost 18 months after defervescence, which terminated gradually without specific therapy. The second patient had similar manifestations over a period of weeks that rapidly resolved after tetracycline therapy. Such phenomena were not previously described in the literature, as far as we know, although similar manifestations were noted in Rocky Mountain spotted fever.

Relapse of rickettsial Mediterranean spotted fever and murine typhus after treatment with chloramphenicol.

In the years 1975-1984, 132 patients with rickettsial Mediterranean spotted fever and murine typhus were treated with chloramphenicol or tetracycline. Among the 24 patients who received chloramphenicol ten relapsed and one failed to respond at all. None of the 108 recipients of tetracycline suffered a relapse. It appears that tetracycline should serve as first-line therapy in several rickettsial diseases.