Suppression and regression of choroidal neovascularization by polyamine analogues

PURPOSE: Polyamine analogues inhibit tumor growth in vitro and in vivo, and oligoamines with a chain length of 10, 12, or 14 are particularly potent. This study was conducted to investigate the effect of the decamines CGC-11144 and CGC-11150 in a mouse model of choroidal neovascularization (CNV). METHODS: Mice with laser-induced rupture of Bruch's membrane were given intraperitoneal, intravitreous, or periocular injection of CGC-11144, CGC-11150, or vehicle, and after 14 days, they were perfused with fluorescein-labeled dextran, and the area of CNV was measured on choroidal flatmounts by image analysis. In some groups of mice, treatments were started 7 days after rupture of Bruch's membrane to determine the effect of the agent on established CNV. Electroretinograms (ERGs) were performed to assess the effects on retinal function, and histopathology was used to evaluate retinal structure. RESULTS: Intraperitoneal injection of 10 or 20 mg/kg CGC-11144 or CGC-11150 resulted in small but significant reductions in the area of CNV. Intravitreous injection of 20 microg CGC-11144 or CGC-11150 on days 0 and 7 after rupture of Bruch's membrane resulted in a approximately 40% reduction in the area of CNV, with a similar reduction after periocular injections of 0.2 mg CGC-11144 three times a week for 2 weeks. Both intravitreous and periocular delivery of CGC-11144 also caused significant regression of established CNV. Within 2 days of periocular injection of CGC-11144, there was apoptosis in CNV lesions, but not in normal blood vessels or other retinal cells. Periocular injections of d,l-alpha-difluoromethyl-ornithine (DFMO), which decreases polyamine levels by a different mechanism, also inhibited CNV. There was no decline in ERG amplitudes or abnormal retinal morphology after daily injections of 0.2 mg CGC-11144 for 2 weeks, but a single intravitreous injection compromised retinal structure and function. CONCLUSIONS: Periocular delivery of the polyamine analogues may be a useful approach for the treatment of CNV.     

Molecular study of HCV detection,genotypes and their routes of transmission in North West Frontier Province,Pakistan

Objective

To determine hepatitis C virus (HCV) genotypes and explore the associated risk factors in chronic HCV patients.

Methods

A total of 116 patients with chronic hepatitis C were subjected to polymerase chain reaction (PCR) based detection out of which 112 chronic HCV patients [53 male (47.32%), 59 female (52.68%); mean age (43.76±16.40) years; mean BMI (23.8±3.9) kg] were enrolled in this study. The frequency of 6 HCV genotypes and associated risk factors were evaluated from five districts of North West Frontier Province (NWFP).

Results

Genotype 3 was the most prevalent in 73 samples (65.17%) followed by genotype 1 in 24 (21.42%) and genotype 2 in 13 (11.60%) samples. Genotype 3 had significantly high prevalence (P=0.000 2). The results showed that 48 (42.85%) samples were infected with HCV 3a; 25 (22.32%) with 3b; 14 (12.50%) with 1a; 10 (8.92%) with 1b; 11 (9.82%) with 2a; 2 (1.78%) with 2b; and 2 were untypable. The distribution of HCV genotypes in Mardan, Charsadda, Peshawar, Sawabi and Nowshehra districts was different. Use of unsterile equipment for medication, barbers and previous history of hospitalization were the main risk factors for HCV transmission.

Conclusions

Genotype 3a and 3b, 1a, 1b and 2a are the common genotypes in NWFP. Genotype 4, 5, and 6 can not be found in a single sample. The level of awareness about various modes of transmission of HCV among the population is found to be very low.     

Changes in the amplitude and timing of the hemodynamic response associated with prepulse inhibition of acoustic startle

Disruption of the early stages of information processing in limbic brain circuits may underlie symptoms of severe neuropsychiatric disorders. Prepulse inhibition of acoustic startle (PPI) is diminished in many of these disorders and may reflect the disruption of this CNS function. PPI is associated with brain activity in many of the same regions in humans as it is in laboratory animals, suggesting that neuroimaging studies in humans may help localize deficits that can then be elucidated in animal models. In this article, we employed a rapid presentation event-related design during continuous EPI BOLD scanning to examine hemodynamic response functions (HRFs) associated with PPI. Fourteen healthy participants listened to 100 pulse alone and 100 prepulse combined with pulse (prepulse-pulse) trials. PPI is the normalized difference in the startle response to the two trial types. Following the prepulse-pulse trials, the amplitudes of the HRFs in auditory cortices and in the anterior insula were increased, while in the cerebellum, thalamus and anterior cingulate, they were decreased, relative to the pulse alone trials. In addition, the timing of the prepulse-pulse responses was delayed in the auditory cortices, anterior insula and cerebellum. Finally, PPI measured outside the scanner was predicted by the difference in BOLD responses between trial types in the anterior insula and in the cerebellum. The results suggest that prepulse inhibition, and by extension early stages of information processing, modulate both the amplitude as well as timing of neural activity.     

Detection and identification of mouse mammary tumor virus-like DNA sequences in blood and breast tissues of breast cancer patients

Mouse mammary tumor virus (MMTV) is a well-known cause of mammary tumors in mice transmitted as endogenous proviruses or exogenously as infectious virions. The hypothesis that a retrovirus homologous to MMTV is involved in human breast cancers has resulted in renewed interest in the etiology of human breast cancer. Therefore, the detection of MMTV-like exogenous sequences in 30–40 % of invasive breast cancer has increased attention towards this hypothesis. To detect the prevalence of MMTV in Pakistani population, 666-bp-long MMTV envelop and 630-bp LTR sequences were amplified from breast cancer patient samples (tissue biopsies and peripheral blood) using mouse with mammary tumor as control. MMTV-like virus env and LTR DNA sequences were detected in 20 and 26 % of breast tumor samples, respectively, from the total of 80 breast cancer patients’ blood and tissue samples. No significant association was observed between age, grade of disease, and lymph node involvement with the prevalence of MMTV-like sequences. Our data add to the growing number of studies implicating MMTV-like virus in human breast cancer, but still clear causal association of MMTV to breast cancer remains to be reputable.     

A lifestyle management programme focused on exercise,diet and physiotherapy support for patients with hip or knee osteoarthritis and a body mass index over 35: A qualitative study

The Lifestyle Management Programme (LMP) is an exercise and weight management programme with physiotherapy support for people with hip or knee osteoarthritis (OA) and a body mass index (BMI) over 35. This qualitative study explored views and experiences of the LMP among patients and professionals, and offers insight for future programmes. Five referring clinicians and six delivering professionals participated in focus groups. Three referring GPs and nine patients who attended the LMP took part in semi‐structured interviews. Topics included: referral, reasons for taking up and continuing the programme or not, and experiences and outcomes. Framework method was used to analyse the qualitative data. Overall, patients and professionals valued the multidisciplinary nature of the LMP. However, professionals explained feeling guilty about delaying patients on the orthopaedic waiting list and believed that the programme should be redirected to those with less severe OA and a lower BMI. Referring clinicians differed in their interpretation of the referral criteria and expressed varying levels of autonomy when making referrals. Patients referred after a consultation with their general practitioner appeared to be more satisfied with the referral process. Patients were also encouraged by the opportunity to improve health, their likelihood of surgery and social benefits. However, patients were discouraged by inconvenience, cost, lack of readiness to change and embarrassment. In conclusion, shared decision‐making about lifestyle management without delaying orthopaedic opinion is preferable, and more psychological support may increase participation. Importantly, the programme may be better focused on rehabilitation for patients with a lower BMI and less severe symptoms.