Infectious complications of the primary immunodeficiencies

The primary manifestation of the immunodeficiencies is undue susceptibility to infection. This means too many, too severe, too prolonged, too complicated and too unusual infections. Infections in immunodeficiency have a characteristic cause depending on the nature of the immune deficiency. Antibody deficiencies are associated with infections with gram-positive infections. Cellular immune deficiencies are associated with mycobacterial, protozoan, fungus, virus, and opportunistic bacterial infection. Phagocytic disorders are associated with staphylococcal, fungal, and gram-negative organisms. Complement disorders are associated by neisserial infections. Infections have also been implicated in the pathogenesis of some immunodeficiencies in some circumstances. These include human T lymphotropic virus type III (HTLV-III), rubella virus, cytomegalovirus, and Epstein-Barr virus. Several infectious syndromes in specific immunodeficiencies have been identified. Examples include enteric cytopathic human orphan (ECHO) virus encephalitis in agammaglobulinemia, and meningococcal meningitis in C6 deficiency. Infections can also be induced by live vaccines given in immunodeficiency (e.g., paralytic polio in agammaglobulinemia.) Unusual infectious syndromes will be illustrated including parainfluenza infection in severe combined and immunodeficiency, Legionella pneumonia in chronic granulomatous disease, and Cryptosporidium infection in hyper-IgM immunodeficiency.     

Primary gastrointestinal stromal tumor of the esophagus in an HIV-positive patient

We describe a rare case of malignant gastrointestinal stromal tumor (GIST) of the esophagus presenting in an HIV-positive man. Not only did the tumor arise from an unusual anatomic site for GIST, namely, the esophagus, but it also had a predominant epithelioid cell morphology that is uncommon and preferentially associated with aggressive behavior. Exhaustive immunohistochemical studies showed strong reactivities to the classic GIST marker, CD34, and to the current more sensitive and more specific GIST marker, CD117/ c-kit protein. This immunophenotype corresponded to that of stromal tumors arising in the more common sites like stomach and small intestine as well as to that of a reported series of esophageal GISTs in the general population. Mutations of the c-kit protein was detected in the tumor, confirming previous observations. This further documents that esophageal GIST and the more common benign esophageal spindle cell lesions are pathologically distinct entities and despite its rarity, esophageal GIST should be recognized by pathologists and clinicians. The occurrence of this tumor in an HIV-positive patient is coincidental, and it resulted in an extremely unusual metastatic site that has not been reported for GISTs.     

Synergistic antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of Vibrio vulnificus infection.

BACKGROUND AND PURPOSE: Vibrio vulnificus causes primary bacteremia and necrotizing wound infection, leading to high morbidity and mortality in humans. This study aimed to evaluate the antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of V. vulnificus infection. METHODS: We investigated the dynamics of proinflammatory cytokines and their modulation by antimicrobial agents using a murine model of V. vulnificus infection. The change in cytokine levels was followed over a time course to identify the antimicrobial activity of the drugs against V. vulnificus. BALB/c female mice were challenged with an intraperitoneal infection using a clinical invasive isolate of Vv05191, and their cytokine levels were assayed over various time points. RESULTS: Serum levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6 post-infection were found to be inoculum dose-dependent and positively correlated to the subsequent fatality rate in the infected mice. With an inoculum of 6.6 x 10(6) colony-forming units and intraperitoneal administration of cefotaxime, minocycline, or both, the serum and peritoneal fluid cytokine levels increased and then declined gradually. Comparison of the 3 antimicrobial regimens revealed that the magnitude of reduction in cytokine levels was greatest in mice treated with cefotaxime-minocycline combination. Moreover, the peritoneal fluid cytokine level in the combination group was significantly lower than that in the groups treated with minocycline or cefotaxime alone. CONCLUSIONS: The current results support the superiority of the combination therapy in treating invasive V. vulnificus infections.     

Ventral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signaling.

Although Hedgehog (HH) signaling plays a critical role in patterning the ventral midbrain, its role in early midbrain specification is not known. We examined the midbrains of sonic hedgehog (Shh) and smoothened (Smo) mutant mice where HH signaling is respectively attenuated and eliminated. We show that some ventral (Evx1+) cell fates are specified in the Shh-/- mouse in a Ptc1- and Gli1-independent manner. HH-independent ventral midbrain induction was further confirmed by the presence of a Pax7-negative ventral midbrain territory in both Shh-/- and Smo-/- mice at and before embryonic day (E) 8.5. Midbrain signaling centers are severely disrupted in the Shh-/- mutant. Interestingly, dorsal markers are up-regulated (Wnt1, Gdf7, Pax7), down-regulated (Lfng), or otherwise altered (Zic1) in the Shh-/- midbrain. Together with the increased cell death seen specifically in Shh-/- dorsal midbrains (E8.5-E9), our results suggest specific regulation of dorsal patterning by SHH, rather than a simple deregulation due to its absence.     

Changes in dielectric properties at 460 kHz of kidney and fat during heating: importance for radio-frequency thermal therapy

We have developed a system to measure the changes due to heating to high temperatures in the dielectric properties of tissues in the radio-frequency range. A two-electrode arrangement was connected to a low-frequency impedance analyser and used to measure the dielectric properties of ex vivo porcine kidney and fat at 460 kHz. This frequency was selected as it is the most commonly used for radio-frequency thermal therapy of renal tumours. Tissue samples were heated to target temperatures between 48 and 78 degrees C in a hot water bath and changes in dielectric properties were measured during 30 min of heating and 15 min of cooling. Results suggest a time-temperature dependence of dielectric properties, with two separate components: one a reversible, temperature-dependent effect and the other a permanent effect due to structural events (e.g. protein coagulation, fat melting) that occur in tissues during heating. We calculated temperature coefficients of 1.3 +/- 0.1% degrees C(-1) for kidney permittivity and 1.6% degrees C(-1) for kidney conductivity, 0.9 +/- 0.1% degrees C(-1) for fat permittivity and 1.7 +/- 0.1% degrees C(-1) for fat conductivity. An Arrhenius model was employed to determine the first-order kinetic rates for the irreversible changes in dielectric properties. The following Arrhenius parameters were determined: an activation energy of 57 +/- 5 kcal mol(-1) and a frequency factor of (6 +/- 1) x 10(34) s(-1) for conductivity of kidney, an activation energy of 48 +/- 2 kcal mol(-1) and a frequency factor of 6 x 10(28) s(-1) for permittivity of kidney. A similar analysis led to an activation energy of 31 +/- 4 kcal mol(-1) and a frequency factor of (4.43 +/- 1) x 10(16) s(-1) for conductivity of fat, and an activation energy of 40 +/- 4 kcal mol(-1) and a frequency factor of 4 x 10(22) s(-1) for permittivity of fat. Structural events occurring during heating at different target temperatures as determined by histological analyses were correlated with the changes in the measured dielectric properties.     

"Waste" follicular aspirate from fertility treatment--a potential source of human germline stem cells?

Fertility clinics worldwide routinely produce a large volume of 'waste' follicular aspirate, which is potentially an abundant source of immature ovarian follicles. Current attempts to cultivate these further in vitro to yield viable mature oocytes for fertility treatment have not yet achieved much success. Instead, recent lines of evidence have emerged that are suggestive of a potential stem cell niche within such immature ovarian follicles. The recent discovery of follicular renewal and putative germ-line stem cells within the postnatal mammalian ovary shook the foundations of reproductive biology by challenging the established dogma that mammalian females lose the capacity for germ cell renewal during fetal life, such that a fixed reserve of germ cells (oocytes) enclosed within follicles is endowed at birth. More intriguingly, another recent study in the Drosophila model provided compelling evidence that somatic progenies (nurse cells) of germ-line stem cells had the ability to revert back to the stem-cell-like state. This introduces the exciting possibility that within the mammalian ovarian follicle, similar somatic progenies of germ-line stem cells may also possess a greater intrinsic ability to revert back into functional stem cells. If this is the case, then a favored candidate would be the cumulus/granulosa of immature ovarian follicles, since such cells are true homologues of nurse cells found within the Drosophila ovary. The successful elucidation of a human germ-line stem cell niche within immature ovarian follicles is likely to have huge ramifications in stem cell biology and regenerative medicine.     

In vitro activity and beta-lactamase stability of the new oral cephalosporin Bay v 3522

The activity of the new oral cephalosporin Bay v 3522 was compared to that of six other beta-lactam agents. Bay v 3522 inhibited methicillin-susceptibleStaphylococcus aureus andStaphylococcus epidermidis at 2 µg/ml, compared to MICs of 8 µg/ml for the other cephalosporins tested. It was more active againstStreptococcus pyogenes (MIC 0.06 µg/ml) than cefuroxime, cefixime, cephalexin and cefaclor. Groups B, C and G streptococci were inhibited at 0.12 µg/ml, while the MIC90 forStreptococcus bovis and viridans streptococci was 0.5 and 2 µg/ml, respectively. The MIC90 for enterococci andListeria monocytogenes was 8 µg/ml.Clostridium perfringens was inhibited by 0.12 µg/ml, but mostBacteroides spp. were resistant. The MIC90 for beta-lactamase positiveEscherichia coli (producing primarily TEM-1) was >64 µg/ml and for beta-lactamase negative strains 16 µg/ml. The MIC90 for high-level beta-lactamase producingKlebsiella pneumoniae was >64 µg/ml versus 4 µg/ml for other isolates. The MIC90 forMoraxella catarrhalis was 2 µg/ml, forHaemophilus influenzae 1 µg/ml, and forNeisseria gonorrhoeae 4 µg/ml.Enterobacter cloacae, Citrobacter freundii, Proteus mirabilis, Providencia spp. andPseudomonas aeruginosa were resistant. Bay v 3522 was destroyed by TEM-1, SHV-1, TEM-3 and P99 beta-lactamases.     

APC I1307K and the E1317Q variants are not present in Chinese colorectal cancer patients.

PURPOSE: The APC I1307K and E1317Q variants predispose to colorectal adenomas and carcinomas in Caucasians, but data are lacking in Asians. METHODS AND RESULTS: We sequenced the APC gene from codons 1261 to 1409 and found none of 147 Chinese, 20 Malay, and 11 Indian colorectal cancer patients in Singapore to carry the APC I1307K or E1317Q variants. CONCLUSION: These variants are rare in these Asian populations, and play little role in colorectal cancer causation in Chinese.