Bacteremia and fungemia in patients with advanced human immunodeficiency virus (HIV) infection in Taiwan

To understand the etiology and clinical outcome of bacterial and fungal sepsis in patients with advanced human immunodeficiency virus (HIV) infection in Taiwan, we conducted a prospective study of nonmycobacterial bacteremia and fungemia in HIV-infected patients with fever who were admitted to a university hospital in Taiwan during a 42-month period. Of 210 patients, 41 (19.5%) had a total of 52 episodes of sepsis due to nonmycobacterial bacteria or fungi, or both (15.5% of 336 episodes of fever). All but one patient had acquired immunodeficiency syndrome (AIDS), and the mean CD4 lymphocyte count was 29/microL (range, 0-321/microL). A total of 57 pathogens (39 bacteria and 18 fungi) were isolated from blood; polymicrobial sepsis due to both bacteria and fungi occurred in four episodes. Nontyphoid Salmonella (NTS) was the most common cause of community-acquired bacteremia (24/30, 80%). Staphylococcus aureus bacteremia was diagnosed in three episodes while Streptococcus pneumoniae bacteremia was found in only one. Cryptococcus neoformans was the most common cause of fungemia and was responsible for 12 episodes, while fungemia due to Penicillium marneffei and Histoplasma capsulatum, two emerging fungi in Taiwan, were diagnosed in four cases and one case, respectively. Nine episodes, eight of bacteremia and one of candidemia, were nosocomial. The overall in-hospital mortality was 29%, and nosocomial sepsis was associated with a higher mortality rate (56%, p = 0.02). The mean duration of survival after recovery from initial sepsis was 426 days. We conclude that NTS bacteremia was the most common cause of sepsis in patients with advanced HIV infection in Taiwan and clinicians caring for such patients should watch for emerging fungal infections. Nosocomial sepsis was associated with a high mortality rate. The mean survival duration after recovery from sepsis of our patients was short.     

Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations

17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a compound that is proposed for clinical development, shares the ability of geldanamycin to bind to heat shock protein 90 and GRP94, thereby depleting cells of p185erbB2, mutant p53, and Raf-1. Urine and plasma from mice treated i.v. with 17AAG contained six materials with absorption spectra similar to that of 17AAG. Therefore, in vitro metabolism of 17AAG by mouse and human hepatic preparations was studied to characterize: (a) the enzymes responsible for 17AAG metabolism; and (b) the structures of the metabolites produced. These materials had retention times on high-performance liquid chromatography of approximately 2, 4, 5, 6, 7, and 9 min. When incubated in an aerobic environment with 17AAG, murine hepatic supernatant (9000 x g) produced each of these compounds; the 4-min metabolite was the major product. This metabolism required an electron donor, and NADPH was favored over NADH. Metabolic activity resided predominantly in the microsomal fraction. Metabolism was decreased by approximately 80% in anaerobic conditions and was essentially ablated by CO. Microsomes prepared from human livers produced essentially the same metabolites as produced by murine hepatic microsomes, but the 2-min metabolite was the major product, and the 4-min metabolite was next largest. There was no metabolism of 17AAG by human liver cytosol. Metabolism of 17AAG by human liver microsomes also required an electron donor, with NADPH being preferred over NADH, was inhibited by approximately 80% under anaerobic conditions, and was essentially ablated by CO. Liquid chromatography/mass spectrometry analysis of human and mouse in vitro reaction mixtures indicated the presence of materials with molecular weights of 545, 601, and 619, compatible with 17-(amino)-17-demethoxygeldanamycin (17AG), an epoxide, and a diol, respectively. The metabolite with retention time of 4 min was identified as 17AG by cochromatography and mass spectral concordance with authentic standard. Human microsomal metabolism of 17AAG was inhibited by ketoconazole, implying 3A4 as the responsible cytochrome P450 isoform. Incubation of 17AAG with cloned CYP3A4 produced metabolites 4 and 6. Incubation of 17AAG with cloned CYP3A4 and cloned microsomal epoxide hydrolase produced metabolites 2 and 4, with greatly decreased amounts of metabolite 6. Incubation of 17AAG with human hepatic microsomes and cyclohexene oxide, a known inhibitor of microsomal epoxide hydrolase, did not affect the production of metabolite 4 but decreased the production of metabolite 2 while increasing the production of metabolite 6. These data imply that metabolite 2 is a diol and metabolite 6 is an epoxide. Mass spectral fragmentation patterns and the fact that 17AG is not metabolized argue for the epoxide and diol being formed on the 17-allylamino portion of 17AAG and not on its ansamycin ring. These data have implications with regard to preclinical toxicology and activity testing of 17AAG as well as its proposed clinical development because: (a) production of 17AG requires concomitant production of acrolein from the cleaved allyl moiety; and (b) 17AG, which was not metabolized by microsomes, has been described as being as active as 17AAG in decreasing cellular p185erbB2.     

F-18 FDG whole-body positron emission tomography scan in primary breast sarcoma

Three patients with primary breast sarcoma showed intense F-18 FDG breast uptake on the whole-body scan. In two patients the uptake was irregular and associated with cold foci that corresponded to hypodense lesions noted on the chest CT; these represented areas of pathologically demonstrated tumor necrosis. There was also intense FDG uptake in pulmonary, axillary, and supraclavicular lymph node metastases. All lesions were confirmed by CT scan of the chest. Thus F-18 FDG positron emission tomographic scanning accurately staged the tumors in these two patients, and it documented local recurrence in the third patient. Histopathologic examination showed evidence of a high-grade sarcoma, a primary rhabdomyosarcoma, and a malignant cystosarcoma phyllodes of the breast. Similar to breast carcinoma, F-18 FDG whole-body positron emission tomographic imaging could be useful in diagnosing and staging primary breast sarcomas.     

Halohydrin analogues of cryptophycin 1: synthesis and biological activity

The chloro-, bromo-, and iodo-derivatives 2-4 of the antimitotic drug cryptophycin 1 were synthesized by opening the epoxide ring. The biological activities of the compounds were tested in an in vitro microtubule assembly and a cell proliferation assay. The chloro-derivative 2 showed lower activity in the tubulin assay compared to 3 and 4, but they all showed similar inhibition in the proliferation assay.     

The Notch signalling pathway in hair growth

The Notch signalling pathway is an important mediator of cell fate selection whose involvement in epidermal appendage formation is now becoming recognised. Hair follicle development and hair formation involve the co-ordinated differentiation of several different cell types in which Notch appears to have a role. We report intricate expression patterns for the Notch-1 receptor and three ligands, Delta-1, Jagged-1 and Jagged-2 in the hair follicle. Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1 is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode. Expression of Jagged-1 or Jagged-2 overlaps Notch-1 expression at all stages. In mature follicles, Jagged-1 and Jagged-2 are expressed in complementary patterns in the follicle bulb and outer root sheath, Jagged-1 in suprabasal cells and Jagged-2 predominantly in basal cells. In the follicle bulb, Jagged-2 is localised to the inner (basal) bulb cells next to the dermal papilla which do not express Notch-1, whereas Jagged-1 expression in the upper follicle bulb overlaps Notch-1 expression and correlates with bulb cell differentiation into hair shaft cortical and cuticle keratinocytes.     

Forensic implications and medical-legal dilemmas of maternal versus fetal rights

The purpose of this paper is to review the issue of fetal rights from primarily a legal perspective, with consideration of morals and professional ethics. The practice of medicine is fraught with numerous bioethical dilemmas. These dilemmas often leave the physician wondering if he has made the correct decision. A physician's morals and professional ethics may influence his or her decision in resolving bioethical dilemmas. The case example is a 34-year-old female with a 41-week intra-uterine pregnancy. The mother was refusing induction of labor. Without the labor induction, the fetus may die. Despite this risk, the mother desired to pursue a vaginal delivery. The AMA's ethics state that a competent, pregnant mother's wishes should prevail and the court should not be involved unless there are unusual circumstances. The mother in the case example was competent and informed consent was provided. Case law does not specifically address the dilemma of the case example. However, there is case law regarding court-ordered cesarean sections which reveals different opinions. The difference in court opinion encompasses the relative degree of weight given to the fetus's right to be born healthy and alive versus the mother's privacy rights. Some courts describe this "balancing test," whereas others state that the mother's privacy rights prevail unless there are exceptional circumstances, which will be extremely rare. The fetus has acquired rights in other areas of the law; for example, abolishment of the intra-family immunity doctrine and the definition of murder in most states. In considering the legal arena of fetal versus maternal rights, a decision tree is presented to assist physicians in assessing cases of a pregnant mother refusing medical treatment. There is no precise demarcation in assessing fetal and maternal rights. The greater the degree of fetal viability, the greater degree of fetal rights. Consideration must also be given to the relative degree of invasiveness to the mother for the proposed procedure; the more invasive, the greater degree of maternal rights. Each case must be evaluated on an individual basis and the decision tree can assist a clinician with this process.     

Topical ondansetron attenuates nociceptive and inflammatory effects of intradermal capsaicin in humans

Topical application of the 5-HT3 receptor antagonist ondansetron (50-250 microg) delivered in a pluronic lecithin organogel vehicle (PLO, 0.5 ml) produced dose-dependent attenuation of nociceptive and inflammatory effects of intradermally injected capsaicin (10 microg/10 microl) in humans. Significant, dose-dependent analgesic effects were produced by 100 microg and 250 microg doses of ondansetron; these doses also reduced mechanical hyperalgesia produced by capsaicin. However, only 250 microg dose of ondansetron diminished capsaicin-induced inflammatory flare.     

Frequent somatic mutations in serine/threonine kinase 11/Peutz-Jeghers syndrome gene in left-sided colon cancer

We analyzed somatic mutation and loss of heterozygosity (LOH) in the serine/threonine kinase 11 (STK11)/Peutz-Jeghers syndrome gene in 49 colorectal tumors in three different stages of a dysplasia-carcinoma sequence. We detected LOH in 10 of 19 (52.6%) informative colorectal cancers at loci D19S886 and/or D19S883, but no LOH was observed in 25 informative adenomas. We detected a total of 9 somatic mutations [7 of 13 (53.8%) left-sided colon cancers and 2 of 7 (28.6%) left-sided adenomas with high-grade dysplasia], but no mutations were detected in right-sided colon tumors. Of the nine mutations, one was a frameshift mutation (the same mutation detected in Peutz-Jeghers syndrome family previously), and the other eight were missense mutations. This results indicate that STK11 is a tumor suppressor gene and that genetic changes of STK11 play an important role in left-sided colon cancer carcinogenesis.     

Course of psychiatric and substance abuse syndromes co-occurring with bipolar disorder after a first psychiatric hospitalization

BACKGROUND: Patients with bipolar disorder frequently meet criteria for other psychiatric and substance abuse diagnoses. To clarify relationships among these disorders, the authors examined the course of syndromes co-occurring with bipolar disorder for 12 months after a first hospitalization. METHOD: Seventy-seven patients were recruited from consecutive inpatient admissions who met DSM-III-R criteria for bipolar disorder, manic or mixed with psychosis. The 12-month syndromal course of co-occurring DSM-III-R alcohol and drug abuse disorders, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and other anxiety disorders were longitudinally recorded. RESULTS: The rates of all syndromes, except other anxiety disorders, were elevated. OCD demonstrated an interval course that frequently mirrored the course of the bipolar disorder. The courses of PTSD and substance abuse syndromes were separate from that of the bipolar disorder in many of those with both syndromes. Alcohol and drug abuse syndromes were strongly correlated. CONCLUSION: The obsessive-compulsive syndrome may represent an alternative expression of bipolar disorder in some patients. In contrast, PTSD appears to represent a truly separate disorder, which is possibly more prevalent in bipolar patients due to a shared risk factor. Substance abuse does not appear to simply result from attempts at self-medication or from the impulsivity of mania. These results suggest that future studies examining the course of syndromes co-occurring with bipolar disorder are warranted.