An evaluation of chemical photoreactivity and the relationship to phototoxicity

The existing regulatory guidance for photosafety testing of new drug products states that studies are warranted for those chemicals that both absorb light in the range of 290–700 nm, and that are either applied locally/topically, or “reach” (EMEA)/“significantly partition” (FDA) to the skin or eyes. The initial in vitro study recommended for the assessment of phototoxic potential is the 3T3 Neutral Red Uptake (NRU) Assay. The current study was undertaken to establish superior triggers for the initiation of biological photosafety testing. In this study, photophysical and photochemical parameters for 40 drug or drug-like molecules were studied. Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and a fivefold cross-validation PLS algorithm were used to evaluate the relationship between subsets of photophysical and photochemical parameters with the 3T3 NRU PIF/MPE (Photo Irritation Factor/Mean Photo Effect) results. The parameters most indicative of a 3T3 NRU positive PIF or MPE score were the extent of degradation in solution, the quantum yield of formation of singlet oxygen and the relative formation of superoxide anion. The results demonstrate that while absorption of light is critical to the induction of a light-induced process, it is the resultant events that may be used to predict the 3T3 NRU assay result. It is therefore proposed that the trigger for photosafety testing be revised to include a molecular basis for photoreactivity. From this limited investigation, estimated thresholds leading to 3T3 NRU positive results due to photodegradation, formation of singlet oxygen quantum yield or a relative superoxide anion formation value are proposed.     

Deoxyribonucleic acid-damaged sperm in cryopreserved-thawed specimens from cancer patients and healthy men

A similarity was found between the percentage of thawed, DNA-damaged spermatozoa in cancer patients and that in candidates to become sperm bank donors who had low sperm cryofreezability. Both groups were significantly different from the sperm bank donor group. It is suggested that the higher rate of DNA fragmentation in sperm from cancer patients compared with sperm bank donors is apparently a result of selecting donors by the level of sperm cryofreezability (i.e., high), rather than a direct effect of an existing malignancy.     

The evidence for physiologic management of the active phase of the first stage of labor

The active phase of first stage labor is generally defined as the period between 3 cm to 4 cm to complete cervical dilatation, in the presence of regular uterine contractions. Most women will experience this portion of labor within hospital obstetric units, where care commonly features restriction to bed, electronic fetal monitoring, early treatment of "slow" labors, and few pain management options beyond epidurals and narcotics. However, the available evidence on appropriate care for healthy childbearing women favors activity in labor, intermittent auscultation, patience from caregivers, and nonpharmacologic methods of pain relief. This article reviews the evidence for care practices that support physiologic labor. Modifying intrapartum care to reflect current evidence will improve women's health, and will require a multilevel approach and consistent midwifery demonstration of the model.     

Does Epidural Analgesia Affect the Rate of Spontaneous Obstetric Lacerations in Normal Births?

The precise relationship between epidural use and genital tract lacerations in normal childbirth is unclear. Data from a clinical trial on measures to lower genital tract trauma in vaginal birth were used for a secondary analysis. The goal was to assess whether epidurals affect the rate of spontaneous obstetric lacerations in normal vaginal births. Maternal characteristics and intrapartum variables were compared in women who did and did not use an epidural in labor, and also in those with and without any sutured lacerations following vaginal birth. Variables that were statistically different in both cases were entered into regression equations for simultaneous adjustment. Epidural use was not an independent predictor of sutured lacerations. Predictors of sutured lacerations included nulliparity, a prolonged second stage, being non-Hispanic white, and an infant birthweight greater than 4000 grams. Elements of midwifery management need further research.     

Minimizing genital tract trauma and related pain following spontaneous vaginal birth

Genital tract trauma is common following vaginal childbirth, and perineal pain is a frequent symptom reported by new mothers. The following techniques and care measures are associated with lower rates of obstetric lacerations and related pain following spontaneous vaginal birth: antenatal perineal massage for nulliparous women, upright or lateral positions for birth, avoidance of Valsalva pushing, delayed pushing with epidural analgesia, avoidance of episiotomy, controlled delivery of the baby's head, use of Dexon (U.S. Surgical; Norwalk, CT) or Vicryl (Ethicon, Inc., Somerville, NJ) suture material, the "Fleming method" for suturing lacerations, and oral or rectal ibuprofen for perineal pain relief after delivery. Further research is warranted to determine the role of prenatal pelvic floor (Kegel) exercises, general exercise, and body mass index in reducing obstetric trauma, and also the role of pelvic floor and general exercise in pelvic floor recovery after childbirth.     

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.