Langerhans cell density and high-grade vulvar intraepithelial neoplasia in women with human immunodeficiency virus infection

BACKGROUND: Decreased numbers of Langerhans cells (LCs) in the cervix of human immunodeficiency virus (HIV)-infected women are believed to contribute to the progression of human papilloma virus (HPV)-related squamous intraepithelial lesions. However, this impairment of local immunity has not been well studied in the vulva. The objective of this study was to compare the S100+ LC density in high-grade vulvar intraepithelial neoplasia (VIN) in HIV-positive and HIV-negative women. METHODS: HIV-positive and HIV-negative patients with high-grade VIN, 48 (55%) and 40 (45%), respectively, were identified by retrospective chart review. Smoking status of patients was noted. The mean LC count per high-power field (HPF) was determined using S100 immunohistochemical staining. In situ hybridization was performed to detect HPV DNA types 16 and 18. RESULTS: Mean S100+ LC counts for HIV-positive and HIV-negative patients were 5.82 and 9.86 per HPF, respectively (p = 0.0026). LC counts in HIV-positive and HIV-negative patients were compared between smoking and nonsmoking groups (HIV-positive p = 0.4812, HIV-negative p = 0.2821). CONCLUSIONS: HIV-positive patients with high-grade VIN had significantly lower LC counts compared with HIV-negative patients. This suggests that local vulvar immunity as evaluated by S100+ LCs is impaired in HIV-positive women, possibly contributing to the progression of HPV-related vulvar lesions.     

Bacterial contamination of ophthalmic solutions used in an extended care facility

AIM: To assess the frequency of contamination of ophthalmic solutions in a long-term care facility and to describe the characteristics of contaminated solutions. METHODS: One hundred and twenty-three ophthalmic solutions used for patient treatment in a long-term care facility were cultured for bacteria. The culture results were analysed according to the therapeutic class of the solution, how long the bottle had been in use and the appearance of the bottle on visual inspection. RESULTS: 10 (8%) of the 123 multiple-dose solutions were contaminated with bacteria: 4 (50%) of 8 steroid-containing anti-inflammatory solutions, 2 (33%) of 6 combination antimicrobial and steroid-containing anti-inflammatory solutions, 2 (6%) of 34 solutions for treatment of glaucoma, and 2 (4%) of 57 medications for "dry eye". None of the mydriatic, miotic or non-combination antimicrobial solutions was contaminated. Proteus mirabilis was identified in 8 (80%) of the 10 contaminated solutions. Only 30% of the contaminated solution bottles were classified as "dirty" bottles when the bottles were visually inspected. Neither the length of time the solutions had been in use nor the appearance of the bottle predicted contamination. CONCLUSIONS: 8% of ophthalmic solutions used in a long-term care facility were contaminated with bacteria, most frequently Proteus mirabilis. Compared with solutions not containing steroids, steroid solutions were 5.8 times more likely to be contaminated (RR = 5.84, 95% CI: 2.42 to 14.10, p<0.002). The frequent contamination during reuse of certain steroid-containing ophthalmic solutions raises the question of whether single-use solutions might be preferred for these and other classes of ocular drugs.     

Dietary uptake kinetics of 2,2',5,5'-tetrachlorobiphenyl in rainbow trout.

The disposition of [UL-(14)C]2,2',5,5'-tetrachlorobiphenyl (TCB) in rainbow trout (Oncorhynchus mykiss) was studied in acute dietary exposures using TCB-contaminated fathead minnows (Pimephales promelas). Trout were sampled at several postfeeding time points and TCB-derived radioactivity was measured in gut contents and selected tissues. Gastric evacuation was exponential with time and was 95% complete within 36 h of feeding. The ratio of activity in upper intestinal tissue to that in blood declined between 6 and 48 h, as did the lumenal contents/tissue ratio. Stomach content lipid declined between 0 and 24 h, while the lipid content of chyme remained relatively constant. These observations are consistent with liquid phase emptying of lipid and TCB to the upper intestine followed by rapid coassimilation. Tissue/blood activity ratios for the stomach, lower intestine, muscle, liver, and kidney were constant and probably represented near equilibrium conditions. The fat/blood activity ratio increased through 96 h, indicating that TCB was redistributing to fat. The lower intestinal tissue/feces activity ratio increased between 6 and 24 h and then declined rapidly. Fecal lipid content also increased between 6 and 24 h, but the amount of this increase was insufficient to explain observed changes in the distribution of TCB-derived activity. A small amount of 3-hydroxy TCB was detected in feces. Generally, however, metabolism had little or no impact on the uptake, distribution or elimination of TCB. Measured assimilation efficiencies exceeded 90% and are the highest ever reported in fish feeding studies with TCB.     

Incidence of metachronous testicular cancer in patients with extragonadal germ cell tumors.

BACKGROUND: The frequency of subsequent testicular cancer (referred to as metachronous testicular cancer) in men who have had previous testicular cancer is relatively high. The rate of metachronous testicular cancer in men with extragonadal germ cell tumors (EGCTs), however, is largely unknown. We conducted a retrospective study of EGCT patients to determine the incidence, cumulative risk, and specific risk factors for metachronous testicular cancers. METHODS: A standardized questionnaire about patient characteristics, the extent of EGCT disease, any second malignancies, and treatments received was completed for 635 patients with EGCTs identified from the medical records of 11 cancer centers in Europe and the United States from 1975 through 1996. Comparisons with age group-specific data from the Saarland, Germany, population-based cancer registry were used to calculate the standardized incidence ratio (SIR). The Kaplan-Meier method was used to analyze survival data and cumulative risk. All statistical tests were two-sided. RESULTS: Sixteen EGCT patients (4.1%) developed metachronous testicular cancers, with a median time between diagnoses of 60 months (range, 14-102 months). The risk of developing metachronous testicular cancers was statistically significantly increased in patients with EGCTs (observed = 16; expected = 0.26; SIR = 62; 95% confidence interval [CI] = 36 to 99) and in subsets of EGCT patients with mediastinal location (SIR = 31; 95% CI = 8 to 59), retroperitoneal location (SIR = 100; 95% CI = 54 to 172), and nonseminomatous histology (SIR = 75; 95% CI = 43 to 123). The cumulative risk of developing a metachronous testicular cancer 10 years after a diagnosis of EGCT was 10.3% (95% CI = 4.9% to 15.6%) and was higher among patients with nonseminomatous EGCTs (14.3%; 95% CI = 6.7% to 21.9%) and retroperitoneal EGCTs (14.2%; 95% CI = 5.6% to 22.8%) than among patients with seminomatous EGCTs (1.4%; 95% CI = 0.0% to 4.2%) and mediastinal EGCTs (6.2%; 95% CI = 0.1% to 12.2%). CONCLUSIONS: Patients with EGCTs, particularly those with retroperitoneal or nonseminomatous tumors, but also those with primary mediastinal EGCTs, are at an increased risk of metachronous testicular cancer.     

Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.

Li Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associated with germ-line mutations in TP53. In a kindred with LFS without an inherited TP53 mutation, we have previously reported a truncating mutation (1100delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser(20). Here, we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from >120 min to 30 min. This effect is abrogated by treatment of cells with a proteosome inhibitor, suggesting that CHK2(R145W) is targeted through this degradation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding tumor specimens, and neither tumor harbors a somatic TP53 mutation. Our observations support the functional significance of CHK2 mutations in rare cases of LFS and suggest that such mutations may substitute for inactivation of TP53.     

Studies of the relationship between molecular structure and hallucinogenic activity

The nature of the stereochemistry and aromatic ring substituents and their importance to biological activity for phenethylamine-type hallucinogens is presented. The possibility of a hydrophobic site to bind to the 4-substituent and its likely geometry is described. A brief discussion of the structure-activity relationships for tryptamines such as psilocin and DMT is also given, with comments about the stereochemistry of alpha-methyltryptamines. Evaluation of a series of N(6)-alkyl-nor-LSD derivatives indicated that selected members such as N(6)-ethyl, allyl and propyl were as potent as, if not more potent than LSD, both in a two-lever drug discrimination assay in rats, and in man. N(6)-alkyl groups longer than n-propyl, such as n-butyl or 2-phenethyl, gave compounds that were greatly reduced in activity.     

Two automated locomotor activity tests for dopamine autoreceptor agonists

In the first test (exploratory activity), pretreated rats explored a novel environment in the dark. The potential autoreceptor agonists apomorphine HCl, N-n-propylnorapomorphine (NPA), and N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and its enantiomers decreased the total distance travelled while at the same time paradoxically increasing the number of discrete movements. This is a very different pattern from that of the typical antipsychotic drugs haloperidol HCl and chlorpromazine HCl, and the atypical antipsychotic drug clozapine, which also decreased the total distance travelled but decreased the number of movements. Both groups decreased the distance/movement. In the second test, rats were habituated to the monitors in the light and then treated with test drug and stimulant (d-amphetamine sulfate or apomorphine HCl). Apomorphine HCl, NPA, and (+)3-PPP antagonized amphetamine-stimulated locomotor behavior (total distance) without antagonizing apomorphine-stimulated behavior, suggesting a presynaptic dopamine autoreceptor agonism. EMD 23448 gave equivocal activity. On the other hand, haloperidol HCl, chlorpromazine HCl, and clozapine decreased both amphetamine- and apomorphine-stimulated behavior, suggesting a postsynaptic dopamine antagonism. 3-PPP and (-)3-PPP showed neither pattern in this test.     

A remote hypertension management program clinical algorithm

IntroductionHypertension is the leading risk factor for death, affecting over one billion people worldwide, yet control rates are poor and stagnant. We developed a remote hypertension management program that leverages digitally transmitted home blood pressure (BP) measurements, algorithmic care pathways, and patient–navigator communications to aid patients in achieving guideline‐directed BP goals.MethodsPatients with uncontrolled hypertension are identified through provider referrals and electronic health record screening aided by population health managers within the Mass General Brigham (MGB) health system. Non‐licensed patient navigators supervised by pharmacists, nurse practitioners, and physicians engage and educate patients. Patients receive cellular or Bluetooth‐enabled BP devices with which they monitor and transmit scheduled home BP readings. Evidence‐based medication changes are made according to a custom hypertension algorithm approved within a collaborative drug therapy management (CDTM) agreement with MGB and implemented by pharmacists.Using patient‐specific characteristics, we developed different pathways to optimize medication regimens. The renin–angiotensin–aldosterone system‐blocker pathway prescribed ARBs/ACE inhibitors first for patients with diabetes, impaired renal function, and microalbuminuria; the standard pathway started patients on calcium channel blockers. Regimens were escalated frequently, adding thiazide‐type diuretics, and including beta blockers and mineralocorticoid receptor antagonists if needed.DiscussionWe have developed an algorithmic approach for the remote management of hypertension with demonstrated success. A focus on algorithmic decision‐making streamlines tasks and responsibilities, easing the potential for scalability of this model. As the backbone of our remote management program, this clinical algorithm can improve BP control and innovate the management of hypertension in large populations.