Systemic Anti-Inflammatory Therapy Aided by Curcumin-Laden Double-Headed Nanoparticles Combined with Injectable Long-Acting Insulin in a Rodent Model of Diabetes Eye Disease.

Therapeutic interventions that counter emerging targets in diabetes eye diseases are lacking. We hypothesize that a combination therapy targeting inflammation and hyperglycemia can prevent diabetic eye diseases. Here, we report a multipronged approach to prevent diabetic cataracts and retinopathy by combining orally bioavailable curcumin-laden double-headed (two molecules of gambogic acid conjugated to terminal carboxyl groups of poly(d,l-lactide-co-glycolide)) nanoparticles and injectable basal insulin. The combination treatment led to a significant delay in the progression of diabetic cataracts and retinopathy, improving liver function and peripheral glucose homeostasis. We found a concurrent reduction in lens aggregate protein, AGEs, and increased mitochondrial ATP production. Importantly, inhibition of Piezo1 protected against hyperglycemia-induced retinal vascular damage suggesting possible involvement of Piezo1 in the regulation of retinal phototransduction. Histologic evaluation of murine small intestines revealed that chronic administration of curcumin-laden double-headed nanoparticles was well tolerated, circumventing the fear of nanoparticle toxicity. These findings establish the potential of anti-inflammatory and anti-hyperglycemic combination therapy for the prevention of diabetic cataracts and retinopathy.

Systemic anti-inflammatory therapy aided by double-headed nanoparticles in a canine model of acute intraocular inflammation.

Novel approaches circumventing blood-ocular barriers in systemic drug delivery are lacking. We hypothesize receptor-mediated delivery of curcumin (CUR) across intestinal and ocular barriers leads to decreased inflammation in a model of lens-induced uveitis. CUR was encapsulated in double-headed polyester nanoparticles using gambogic acid (GA)-coupled polylactide-co-glycolide (PLGA). Orally administered PLGA-GA2-CUR led to notable aqueous humor CUR levels and was dosed (10 mg/kg twice daily) to adult male beagles (n = 8 eyes) with induced ocular inflammation. Eyes were evaluated using a semiquantitative preclinical ocular toxicology scoring (SPOTS) and compared to commercial anti-inflammatory treatment (oral carprofen 2.2 mg/kg twice daily) (n = 8) and untreated controls (n = 8). PLGA-GA2-CUR offered improved protection compared with untreated controls and similar protection compared with carprofen, with reduced aqueous flare, miosis, and chemosis in the acute phase (<4 hours). This study highlights the potential of PLGA-GA2 nanoparticles for systemic drug delivery across ocular barriers.

Neel revisited: the adipocyte, seasonality and type 2 diabetes.

The modern epidemic of obesity and insulin resistance with cardiovascular risk factor clustering is related to the development of type 2 diabetes and cardiovascular disease. Over 40 years ago, Neel postulated that insulin resistance should confer survival benefit. Extrapolating Neel's hypothesis, we propose that the cluster of associated abnormalities also confers survival benefit and is related to metabolic responses seen in seasonally responsive animals. Weight gain in preparation for winter is accompanied by a range of acute metabolic changes virtually identical to the long-term changes seen in type 2 diabetes. In seasonal animals the responses are acute, physiological and protective. In man, similar responses that would once have conferred survival benefit have become chronic, pathological and harmful in modern life. We hypothesise that type 2 diabetes and cardiovascular disease in man are the result of chronic and inappropriate pineal-hypothalamic-adipocyte interactions biologically related to seasonal change.

Clinical and pharmacokinetic aspects of ciprofloxacin in the treatment of acute exacerbations of pseudomonas infection in cystic fibrosis patients.

Twelve cystic fibrosis patients, aged over 18, who had developed an acute respiratory exacerbation and who had Pseudomonas species isolated from their sputum, were entered into a clinical trial involving ciprofloxacin. The dosage regimen was 100 mg iv followed by 500 mg twice daily orally if less than 40 kg in weight and 200 mg iv followed by 750 mg twice daily orally if greater than 40 kg. Ciprofloxacin was well tolerated with no major side effects, except in one patient who withdrew after onset of headaches and generalized aches and pains. Eleven of the 12 patients showed clinical improvement at the end of the treatment period as determined by weight gain, Shwachman Score, Chrispin Norman Score and pulmonary function tests. MICs of Pseudomonas species isolated from the sputum at the start of the trial were in the range 0.25-4 mg/l. During therapy, sensitivity of isolates decreased and did not return to starting levels at the end of a four week follow-up period. Pharmacokinetic parameters were similar to those reported for fasting healthy volunteers by other workers except for bioavailability which was reduced in the non-fasting patients.

Hypnosis: emotions for the tin man (the schizoid personality).

Insight psychotherapy had been ineffective in helping a schizoid patient experience affect. He remained cold, aloof, and without overt expression of affect. When hypnosis was utilized, the patient overtly demonstrated affect. Hence the title for the article--hypnosis was effective in changing the tin man into a person with emotions and feelings. A discussion indicates some possible variables associated with this phenomenon.