Peptide-targeted dendrimeric prodrugs of 5-aminolevulinic acid: A novel approach towards enhanced accumulation of protoporphyrin IX for photodynamic therapy.

Photodynamic therapy (PDT) is a promising approach for the targeted treatment of cancer and various other human disorders. An effective, clinically approved approach in PDT involves the administration of 5-aminolevulinic acid (ALA) to generate elevated levels of the natural photosensitiser protoporphyrin IX (PpIX). The development of prodrugs of ALA is of considerable interest as a means to enhance the efficiency and cell selectivity of PpIX accumulation for PDT applications. In this work a novel peptide-targeted dendrimeric prodrug of 5-aminolevulinic acid (ALA) 13 was synthesised which displays nine copies of ALA on a core structure that is linked to a homing peptide for targeted delivery to a specific cancer cell type. The synthesis was accomplished effectively via a flexible, modular solid phase and solution phase route, using a combination of solid phase peptide synthesis and copper-catalysed azide-alkyne cycloaddition chemistry. The prodrug system shows a sustained and enhanced production of protoporphyrin IX (PpIX) in the MDA-MB-231 cell line that over-expresses the epidernal growth factor receptor (EGFR+) in comparison to equimolar ALA and the corresponding non-targeted ALA dendrimer (nine copies of ALA). This study provides a proof of concept for the development of a new generation of prodrugs for ALA-based photodynamic therapy that can deliver an enhanced ALA payload to specific tissue types.

Flies Without Borders: Lessons from Chennai on improving India's municipal public health services.

India's cities face key challenges to improving public health outcomes. First, unequally distributed public resources create insanitary conditions, especially in slums - threatening everyone's health, as suggested by poor child growth even amongst the wealthiest. Second, devolving services to elected bodies works poorly for highly technical services like public health. Third, services are highly fragmented. This paper examines the differences in the organisation and management of municipal services in Chennai and Delhi, two cities with sharply contrasting health indicators. Chennai mitigates these challenges by retaining professional management of service delivery and actively serving vulnerable populations - while services in Delhi are quite constrained. Management and institutional issues have received inadequate attention in the public health literature on developing countries, and the policy lessons from Chennai have wide relevance.

Measurements of adiposity as prognostic biomarkers for survival with anti-angiogenic treatment in epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group ancillary data analysis of GOG 218.

OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.

Flexible synthesis of cationic peptide-porphyrin derivatives for light-triggered drug delivery and photodynamic therapy.

Efficient syntheses of cell-penetrating peptide-porphyrin conjugates are described using a variety of bioconjugation chemistries. This provides a flexible means to convert essentially hydrophobic tetrapyrolle photosensitisers into amphiphilic derivatives which are well-suited for use in light-triggered drug delivery by photochemical internalisation (PCI) and targeted photodynamic therapy (PDT).

Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS: This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS: One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION: Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER: NCT00262847.

Costs of treatment for elderly women with advanced ovarian cancer in a Medicare population.

OBJECTIVE: To analyze the cost of treating women with advanced stage epithelial ovarian cancer (EOC) undergoing primary debulking surgery (PDS) or neo-adjuvant chemotherapy (NACT). METHODS: The Surveillance, Epidemiology, and End Results (SEER) - Medicare database (1992 to 2009) was used to evaluate the 7-month cost of care following PDS and NACT for advanced EOC. Multivariate analyses were used to evaluate differences between women treated by PDS and NACT on cost and survival. RESULTS: Of the 4506 women eligible for analysis, 82.4% underwent PDS and 17.6% received NACT. Eighty-five percent with stage IIIC and 78.5% with stage IV EOC underwent PDS (p<0.0001). No significant difference in the median cost of care between PDS and NACT existed in women with stage IIIC EOC ($59,801 vs. $59,905). There was a 12% increase in adjusted cost of care for stage IV patients ($63,131 vs. $55,302) who received PDS (p<0.0001). Increasing Charlson score was associated with an increase in 7-month cost of care in both stages. NACT was associated with a decreased 5-year overall survival in women with stage IIIC EOC (HR=1.27, 95% CI: 1.10-1.47) and stage IV EOC (HR=1.19, 95% CI: 1.03-1.37) compared to PDS. CONCLUSION: NACT and PDS are comparable in cost for women with stage IIIC EOC, and PDS is minimally more expensive for women with stage IV EOC. PDS was associated with an increase 5-year overall survival. Future investigations should include cost-effectiveness analyses where additional measures such as quality adjusted life years and propensity scored survival are included.

Racial disparities and patterns of ovarian cancer surgical care in California.

OBJECTIVE: To investigate disparities in the frequency of ovarian cancer-related surgical procedures and access to high-volume surgical providers among women undergoing initial surgery for ovarian cancer according to race. METHODS: The California Office of Statewide Health Planning and Development database was accessed for women undergoing a surgical procedure that included oophorectomy for a malignant ovarian neoplasm between 1/1/06 and 12/31/10. Multivariate logistic regression analyses were used to evaluate differences in the odds of selected surgical procedures and access to high-volume centers (hospitals ≥ 20 cases/year) according to racial classification. RESULTS: A total of 7933 patients were identified: White = 5095 (64.2%), Black = 290 (3.7%), Hispanic/Latino = 1400 (17.7%), Asian/Pacific Islander = 836 (10.5%) and other = 312 (3.9%). White patients served as reference for all comparisons. All minority groups were significantly younger (Black mean age 57.7 years, Hispanic 53.2 years, Asian 54.5 years vs. 61.1 years, p < 0.01). Hispanic patients had lower odds of obtaining care at a high-volume center (adjusted OR (adj. OR) = 0.72, 95% CI = 0.64-0.82, p < 0.01) and a lower likelihood of lymphadenectomy (adj. OR = 0.80, 95% CI=0.70-0.91, p<0.01), bowel resection (adj. OR = 0.80, 95% CI = 0.71-0.91, p < 0.01), and peritoneal biopsy/omentectomy (adj. OR = 0.69, 95% CI = 0.58-0.82, p<0.01). Black racial classification was associated with a lower likelihood of lymphadenectomy (adj. OR = 0.76, 95% CI = 0.59-0.97, p = 0.03). CONCLUSIONS: Among women undergoing initial surgery for ovarian cancer, Hispanic patients are significantly less likely to be operated on at a high-volume center, and both Black and Hispanic patients are significantly less likely to undergo important ovarian cancer-specific surgical procedures compared to White patients.

Live attenuated malaria vaccine designed to protect through hepatic CD8⁺ T cell immunity.

Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients. Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans. Such protection is thought to be mediated by CD8(+) T cells in the liver that secrete interferon-γ (IFN-γ). We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8(+), IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria.

Tc-99m ciprofloxacin scans for detection of tubercular bone infection.

Tc-99m MDP and Tc-99m ciprofloxacin scans were performed in 14 patients with suspected tubercular bone disease and in 2 cases of nontubercular bone infection. In 5 patients the findings were true negative. There were no false positives and 1 was false negative. The sensitivity, specificity, and positive predictive value were found to be 93, 71, and 87.5%, respectively, for detection of bone tubercular lesions. However, the test does not distinguish TB osteomyelitis from other types of osteomyelitis. Delayed 24 hour scans were found useful to differentiate between inflammatory and infective lesions. The aim of this study was to evaluate the usefulness of the Tc-99m ciprofloxacin scan as a means to detect tubercular bone disease.

Ovulatory failure, fertility preservation and reproductive strategies in the setting of gynecologic and non-gynecologic malignancies.

The advances in assisted reproductive technology over time have paralleled the insights gained into the natural history of different gynecologic malignancies. Subgroups of young patients with early stage ovarian cancer, endometrial carcinoma and cervical carcinoma may be considered to be at relatively low risk of recurrence and may be treated conservatively with the aim to preserve fertility when this is of prime concern. Unilateral adnexectomy with preservation of the contralateral ovary and uterus may be appropriate for some patients with epithelial ovarian cancers, and certainly should be the procedure of choice for those young women with borderline tumors and early stage sex cord-stromal and malignant germ cell tumors. Administration of high-dose progestins may obviate the need for immediate hysterectomy in a young patient with a well-differentiated endometrial carcinoma desirous of childbearing. The performance of vaginal radical trachelectomy in conjunction with laparoscopic pelvic lymphadenectomies has emerged as a real breakthrough for a highly select group of young women with early invasive tumors of the cervix. In this review, we also discuss reproductive strategies for women who experience chemotherapy-induced ovulatory failure and also address the potential for ovarian cortex cryopreservation and transplantation, and uterine transplantation, all of which are looming on the horizon.

Reemergence of dengue virus type-3 (subtype-III) in India: implications for increased incidence of DHF & DSS.

BACKGROUND: Dengue virus infection has recently taken endemic proportion in India implicating all the four known dengue serotypes. There was a major dengue outbreak in northern India including Delhi in October- December, 2003 and again in 2004. We have carried out a detailed investigation of the 2004 outbreak by Serosurveillance, RT-PCR, nested PCR, virus isolation and genotyping. We also report the molecular epidemiological investigation of these outbreaks. RESULTS: The serological investigation of 162 suspected serum samples using an in-house dengue dipstick ELISA revealed 11%-IgM, 51%-IgG and 38%-both IgM and IgG antibody positivity. The RT-PCR analysis revealed presence of dengue RNA in 17 samples. Further subtyping and genotyping by nested PCR and nucleotide sequencing of C-prM gene junction revealed the association of subtype III of dengue virus type 3 in the outbreak. CONCLUSION: The sudden shifting and dominance of the dengue virus serotype-3 (subtype III) replacing the earlier circulating serotype-2 (subtype IV) is a point of major concern and may be attributed to increased incidence of DHF and DSS in India.

Human rabies in Delhi.

OBJECTIVE: Analysis of human rabies cases admitted in Infectious Diseases Hospital, Delhi during the course of one year was undertaken to understand the epidemiology of rabies. METHODS: The data was collected using standardized proforma and was analyzed on EPI Info 6.02 software version. A total of 49.8% of the human rabies came from Delhi and rest belonged to adjoining states of UP (30.3%), Haryana (18.3%), Bihar (0.8%), Punjab (0.4%) and MP (0.4%). Children in the age group 5-14 years fell victim to the disease in significantly higher numbers (36.7%) as compared to other age groups. Male Female ratio was 4:1. Biting animals involved were dog (96.7%), jackal (1.7%), cat (0.8%), monkey (0.4%) and mongoose (0.4%). Majority (78.8%) had Category III exposure. Hydrophobia, which is the pathogonomic feature of human rabies, was present in 95% of cases. Remaining (5%) gave history of animal bite and presented with features of aerophobia, photophobia along with fever, weakness in limbs, parasthesia, and/or paralysis. Significantly higher number (93.4%) did not receive any local wound treatment. Most (91.7%) cases never received any vaccination and remaining were inadequately vaccinated; only five had received 10-14 injections of Neural Tissue Vaccine (NTV) and one child who had multiple bites on face, received 5 doses of NTV, local wound treatment and intramuscular ARS on 3rd day. RESULT: The data strongly reveals that people who died due to rabies either did not receive any treatment or were inappropriately and inadequately treated. Hence, there is need to educate the community and the health care professionals about the importance of immediate and adequate post exposure treatment. The data also indicates that the epidemiology of the disease has not changed much over the decades. CONCLUSION: The disease can be prevented with the available tools and all we need to do is to implement them effectively.

Epidemiological characteristics of rabies in Delhi and surrounding areas, 1998.

OBJECTIVE: To describe the epidemiological characteristics of rabies in Delhi in 1998. METHODS: Analysis of the records of hydrophobia cases admitted to the Infectious Diseases Hospital, Delhi (IDH) in 1998. RESULTS: About 46 percent (99/215) of the hydrophobia cases admitted to the IDH in 1998 belonged to Delhi. The remaining came from the adjoining states, both urban and rural areas. In Delhi residents, overall hospitalization rate was 0.81 per 100,000 population. It was significantly higher in 5-14 year old than in other age groups and in males than in females (p <0.0009). Cases occurred round the year. Almost 96 percent cases (206/215) gave history of animal exposure, 13 days to 10 years (median 60 days) before hospitalization. Majority (195/206) had class III exposure. Animals involved were stray dog (193/206 = 90 percent), pet dog, cat, jackal, mongoose, monkey and fox. Most of cases were never vaccinated (78 percent) or inadequately vaccinated (22 percent); only 1 percent each received appropriate wound treatment, or rabies immunoglobulin. CONCLUSIONS: Rabies is a major public health problem in Delhi. Its incidence is significantly higher in 5-14 year old children than in other age groups. The results indicate the need to educate the community and health care workers about the importance of immediate and adequate post-exposure treatment and to start an effective control program for dogs, the principal vector of rabies.

Recent advancements in the treatment of epithelial ovarian cancer.

Important advances in the management of advanced epithelial ovarian cancer have been made in recent years, with much of the knowledge emanating from clinical trials conducted by the Gynecological Oncology Group (GOG). This monograph reviews the trials that have defined current clinical practice and summarizes some innovative techniques and promising new drugs for the future

ClC-2 Cl- channels in human lung epithelia: activation by arachidonic acid, amidation, and acid-activated omeprazole.

ClC-2 Cl- channels represent a potential target for therapy in cystic fibrosis. Key questions regarding the feasibility of using ClC-2 as a therapeutic target are addressed in the present studies, including whether the channels are present in human lung epithelia and whether activators of the channel can be identified. Two new mechanisms of activation of human recombinant ClC-2 Cl- channels expressed in HEK-293 cells were identified: amidation with glycine methyl ester catalyzed by 1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC) and treatment with acid-activated omeprazole. ClC-2 mRNA was detected by RT-PCR. Channel function was assessed by measuring Cl- currents by patch clamp in the presence of a cAMP-dependent protein kinase (PKA) inhibitor, myristoylated protein kinase inhibitor, to prevent PKA-activated Cl- currents. Calu-3, A549, and BEAS-2B cell lines derived from different human lung epithelia contained ClC-2 mRNA, and Cl- currents were increased by amidation, acid-activated omeprazole, and arachidonic acid. Similar results were obtained with buccal cells from healthy individuals and cystic fibrosis patients. The ClC-2 Cl- channel is thus a potential target for therapy in cystic fibrosis.

Trisomy 13 in one fetus from a twin gestation after intracytoplasmic sperm injection. A case report.

BACKGROUND: Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technique used in the treatment of severe male factor infertility. Reports of chromosomal aberrations in some fetuses conceived following ICSI have raised concern that the technique may contribute to the development of genetic disease. CASE: Trisomy 13 occurred in one of twin fetuses of a 28-year-old woman who underwent ICSI. This case is unique because it is the first reported one of an autosomal trisomy complicating one fetus from a twin gestation conceived by ICSI. It is also the first case describing an autosomal trisomy following ICSI in a woman under the age of 35. CONCLUSION: Chromosomal abnormalities associated with ICSI may be accounted for by factors other than advanced maternal age. Chromosomal aberrations may be related to the procedure itself. Therefore, patients should be advised of the possibility of aneuploidy in association with ICSI, and genetic amniocentesis should be considered regardless of maternal age.

Bilateral pheochromocytoma in pregnancy heralding multiple endocrine neoplasia syndrome IIA. A case report.

BACKGROUND: Multiple endocrine neoplasia syndrome type IIA (MEN IIA) has rarely been encountered in pregnancy. CASE: A 22-year-old, nulliparous woman developed bilateral pheochromocytomas during pregnancy. This finding aroused suspicion for MEN IIA, and close endocrinologic follow-up was arranged. Four years later, hyperparathyroidism developed, and the diagnosis was established. The patient underwent prophylactic total thyroidectomy with parathyroid exploration. CONCLUSION: This was the first case of MEN IIA in pregnancy in which the diagnosis was established prior to the development of medullary thyroid cancer, thereby allowing prophylactic thyroidectomy. The presence of bilateral neoplastic disease in young patients may be indicative of a hereditary predisposition to malignancy.

Vaginal hysterectomy as primary treatment of endometrial cancer in medically compromised women.

OBJECTIVE: To study the survival, rates and patterns of recurrence, and perioperative morbidity in medically compromised women with endometrial cancer treated by primary vaginal hysterectomy. METHODS: Fifty-one patients with endometrial cancer treated initially by vaginal hysterectomy between 1977 and 1999 were identified at the University of California, Irvine Medical Center and affiliated hospitals. Data were retrieved from hospital and office records. Statistical analysis, including Kaplan-Meier methods, was performed and the disease-specific survival rates were estimated. This study has 80% power to demonstrate a greater than 20% improvement in 5-year survival over historical controls. RESULTS: Fifty-one women with uterine carcinoma clinically confined to the uterus underwent primary vaginal hysterectomy with (n = 26) or without (n = 25) salpingo-oophorectomy. Eighty-four percent were obese with a body mass index greater than 27. Additional risk factors for surgical complications included hypertension (57%), diabetes mellitus (27%), and cardiovascular disease (18%). One-third of patients had three or more risk factors. Surgical morbidity included one episode of acute hemorrhage necessitating transfusion and abdominal exploration. Blood transfusions were given to four additional patients. There were no perioperative deaths. Five women recurred and expired at a median of 13 months (range 3--53 months) after surgery. The 3- and 5-year disease-specific survival rates were 91.4% and 88.0%, respectively. CONCLUSION: Vaginal hysterectomy for the initial treatment of early-stage endometrial cancer is associated with a high rate of cure and minimal morbidity. Thus, it may be considered a reasonable alternative to the abdominal approach in medically compromised women.