Protection of ovarian function by oral contraceptives in women receiving chemotherapy for Hodgkin's disease

It has been reported by us and by others that after chemotherapy for Hodgkin's disease the ovary contains fewer than 5 primordial and primary follicles per 5 x 5 mm biopsy section. In young women this is associated with premature menopause. We report here that before treatment the tissue contains 18--55 such follicles per biopsy section. When women took combination oral contraceptives throughout the course of MVPP therapy, the posttreatment ovarian biopsy tissue had more than 20 follicles per histologic section. Normal menses were established in the five women who discontinued oral contraceptives at the end of MVPP therapy, and one of them is now pregnant.     

History-Adjusted Marginal Structural Analysis of the Association between Hemoglobin Variability and Mortality among Chronic Hemodialysis Patients

Background and objectives: Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control.Design, settings, participants, & measurements: A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin.Results: In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively.Conclusions: Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.Hemodialysis patients experience substantial changes in hemoglobin concentration over time (1–4). This variability derives both from patterns of care, such as changes in erythropoietin and intravenous iron dosing, as well as from comorbid conditions that either influence sensitivity to these therapies, or that directly affect red cell mass. Recently, we demonstrated an association between increased hemoglobin variability (Hgb-Var) and all-cause mortality among chronic dialysis patients (5).As is the case in all nonrandomized research, the observed association between Hgb-Var and death was subject to potential confounding. Confounding occurs when a variable (or variables) affects the likelihood of exposure (e.g. Hgb-Var) and of outcome (e.g. death), but does not serve as an intermediate between exposure and outcome. Standard methods of statistical adjustment are often sufficient to adjust for these confounders when they do not vary over time compared with their baseline values.Unfortunately, there are instances when application of standard statistical techniques may yield biased associations, such as in the presence of time-dependent confounding. Time-dependent confounders (TDC) are variables that have two different roles that are difficult to distinguish: (1) they influence subsequent exposure and outcome like confounders that are fixed over time, and (2) they also serve as intermediates (or links) between exposure and outcome. Although it is appropriate to adjust for their role as confounders, it is inappropriate to adjust for their role as intermediates on the causal pathway from exposure to outcome. If standard statistical techniques are used to adjust for TDC, they adjust for both roles simultaneously and, therefore, may underestimate true associations owing to the adjustment for the role as a causal pathway factor. For example, if Hgb-Var is both influenced by comorbid conditions and promotes these same conditions as part of the mechanism through which it causes poor clinical outcomes, simple adjustment for these comorbidities would lead to biased estimates of the Hgb-Var outcome relationship. Figure 1 serves to illustrate one potential TDC of the association between Hgb-Var and death, namely intravenous iron administration, which may independently be associated with Hgb-Var and mortality (Figure 1A), and may also serve on the causal pathway (Figure 1B).Open in a separate windowFigure 1.Example of the potential time-dependent confounding influence of intravenous iron on the association between hemoglobin variability (Hgb-Var) and death (A) when intravenous iron affects the degree of Hgb-Var and the likelihood of death and (B) also serves as an intermediate between Hgb-Var and death.The best means to avoid the possibility of time-dependent confounding is through randomization to fixed treatment protocols (9). Extending the prior example, this would mean randomizing subjects to high and low levels of Hgb-Var, and treating each group with equivalent amounts of intravenous iron. Unfortunately, current therapies do not enable randomization of subjects to varying degrees of Hgb-Var. Nonetheless, observational research can take advantage of newer statistical tools, such as history-adjusted marginal structural models (HA-MSM), which enable estimation of less biased measures of association from observational data in the presence of time-dependent confounding (8,10–11).Considering that the prior association may have been biased by the presence of time-dependent confounders, we have reanalyzed our data using HA-MSM to better estimate the causal association between Hgb-Var and mortality.     

World Workshop on Oral Medicine VI: a systematic review of medication‐induced salivary gland dysfunction

The aim of this paper was to perform a systematic review of the pathogenesis of medication‐induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, α‐and β‐adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology.     

Respiratory infection and otitis media visits in relation to pneumococcal conjugate vaccine use in Saskatchewan

BACKGROUND:

In Saskatchewan, pneumococcal conjugate vaccination (PCV) was offered to high-risk children in 2002 and to all infants in 2005.

OBJECTIVE:

To describe trends in the frequency of medical visits for lower respiratory tract infection (LRI) and otitis media (OM) in relation to PCV use during the period 1990 to 2008.

METHODS:

Statistics regarding the number of children covered by the health insurance plan, PCV administration, and medical visits with a diagnostic code associated with LRI and OM were provided by Saskatchewan Health. Monthly rates were analyzed using dynamic state space models.

RESULTS:

In all series, there was a marked seasonal cycle and some higher-than-expected winter peak values, possibly associated with epidemics of specific respiratory viruses. Three abrupt decreases in baseline rate were observed for LRI and the final one, in February 2007, could be related to the increased proportion of children vaccinated with PCV. There was no statistical correlation between PCV use and OM visit frequency.

CONCLUSION:

Many environmental, biological and administrative factors may influence health services use, and an effect of low magnitude of a particular vaccine pertaining to nonspecific outcomes could be obscured in time-series analyses.     

Early sexual initiation: the role of peer norms

OBJECTIVE: To elucidate which components of peer norms influence the process of sexual initiation for young adolescents. Design. Prospective cohort study. Setting. Fourteen elementary and middle schools in an urban public school district. Participants. The 1389 sixth-grade students who completed the questionnaire at the beginning (time 1) and at the end (time 2) of the school year comprise the study sample. Mean age at time 1 was 11.7 years. RESULTS: Of students entering the sixth grade, 30% (n = 416) reported having already initiated sexual intercourse, 5% (n = 74) reported initiating sexual intercourse during the sixth-grade school year (initiated group), and 63% (n = 873) reported not having initiated sexual intercourse by the end of the sixth-grade school year (never group). Demographic comparisons revealed that students in the initiated group were significantly more likely than students in the never group to be older (11.9 years vs 11.6 years), male (58% vs 37%), African-American (70% vs 51%), attending a poorer school (87% vs 85%), and living in an area with a high proportion of single-parent families (45% vs 41%). Self-reports and reports of peers' participation in nonsexual risk behaviors were more common for students in the initiated group. Students in the initiated group were more likely than students in the never group to perceive: 1) a high prevalence of sexual initiation among peers; 2) social gains associated with early sexual intercourse; and 3) younger age of peers' sexual initiation. Students in the never group were more likely to believe that sexually-experienced 12-year-old boys would be negatively stigmatized compared with students in the initiated group. Three predictive models were developed to test the relationship between peer norms and the process of initiation. These models demonstrate that the strongest predictor of sexual initiation in sixth grade is having high intention to do so at the beginning of sixth grade. The strongest predictor of high intention is belief that most friends have already had sexual intercourse. Perceptions of social gain and stigma for sexually-experienced 12-year-old boys act independently of intention to decrease risk of early sexual initiation. CONCLUSION: Early sexual intercourse is not an unplanned experience for many teens. Decisions about initiation are strongly bound to social context with peers playing an important role in creating a sense of normative behavior. Specific components of peer norms impact the process of sexual initiation in both positive and negative ways. Interventions aimed at delaying the onset of sexual initiation need to focus on cohort norms as well as on an individual's perceptions and behaviors.     

Uterus and endometrium: Regeneration processes in rabbit endometrium: a photodynamic therapy model

The origin and process of regeneration in rabbit endo metriumwas evaluated following photodynamic epithelial destructionusing topically applied anilnolevulinic acid (ALA). Selectivedestruction of endometrial epithelium was performed using photodynamictherapy (PDT). ALA was diluted to 200 mg/ml dextran 70 shortlyprior to adininistra tion. A volume of 1.2 ml was injected intothe left uterus. Intrauterine illumination (wavelength 630 nm,light dose 40–80 J/cm²was performed 3 h after drug administration.Tissue morphology was evaluated by light and scanning electronmicroscopy 1, 3, 7 and 28 days post-treatment (three animalsat each dine-point). Regeneration of the endometriwn followingepithelial ablation by PDT was fully activated after 24 h andwas completed after 72 h. Endometrial surface generation occurredby proliferation, originating primarily in deeper regions ofthe glands. Findings from our morphological follow-up studysupport the origin of endometrial regeneration being mainlyfrom undifferentiated stem cells and residual glandular epithelium.     

Photomedicine of the endometrium: experimental concepts

Gynaecological photomedicine offers new diagnostic and therapeuticmethods based on the interaction of light with the reproductiveorgans. One example is photodynamic therapy (PDT) in which photosensitizersare applied systemically or topically for selective endometrialablation. Several studies describing the potential use of PDTfor this application are reviewed. Basic experimental and clinicalaspects of PDT, such as photosensitizer types, application modes,irradiation parameters, optical properties of tissues and photodegradationof photosensitizers are discussed.     

Necrotizing fascitis induced by mosquito bite

Necrotizing fascitis usually occurs after a perforating trauma or sometimes surgery. It is an acute necrotizing process which involves the fascia of the skin. Within one or two days of the causative event the patient experiences pain, oedema and a dusky bluish-red discolouration of the skin with or without bullae formation. These areas become gangrenous usually by the fifth day. Often any specific organisms are not grown on culture, but the common ones that are include beta-haemolytic streptococci, coliforms, enterococci, pseudomonas. Treatment comprises early detection, surgical debridement, intravenous antibiotics and supportive care. We report a case of grossly neglected necrotizing fascitis caused by mosquito bites. Our treatment consisted of intravenous antibiotics, thorough debridement, regular dressings and a split-thickness skin graft. These measures collectively preserved an otherwise hopelessly mutilated upper limb.