Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD.

Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4-/-) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.

The Plate cage Benezech implant as an alternative to autologous bone graft in the treatment of cervical spondylosis: clinical and functional outcome.

Plate cage Benezech (PCB) is a titanium-made implant introduced recently in spinal surgery as a new substitute for autograft in cervical spine interbody fusion. It has a plate attached to the anterior surface of the cage to prevent any displacement of the cage, and to provide additional support in patients with dynamic instability. A small number of studies have shown the PCB cage is safe and efficient. We conducted a retrospective study on 54 consecutive patients with cervical spondylosis who underwent anterior cervical discectomy and interbody fusion (ACDF) with a PCB cage between the year 2001 and 2005 with a mean follow up of 24 months (9-62 months). The mean age was 51 years, 27 patients presented with radiculopathy, 15 patients with myelopathy, and eight patients with both. Clinical and functional outcomes were assessed by using Prolo scale, Japanese orthopaedic association (JOA) score, and Visual analogue scale (VAS). Prolo results were documented good to excellent in 43 (86%) of cases and poor in 7 (14%) of cases. Mean preoperative Prolo scale of 4.7 (SD 1.63) improved postoperatively to 8.22 (SD 2.12.) The average preoperative JOA score was 11.7 (SD 2.51) compared with 15.42 (SD 2.20) postoperatively with a mean recovery rate of 76.3%. VAS score improved from 6.65 (SD 1.77) to 1.76 (SD 2.40). All the results were statistically significant (p-value <0.0001).This study suggests that Plate cage Benezech implant is a safe and effective device for anterior cervical discectomy and interbody fusion.

Nephrotoxicity of semustine (methyl-CCNU) in patients with malignant melanoma receiving adjuvant chemotherapy.

The nephrotoxicity of semustine (methyl-CCNU) has been studied in 45 adult patients with surgically resected Stage I or II malignant melanoma who received this drug as adjuvant chemotherapy. Abnormalities of renal function (including three cases of renal failure) were noted in seven of 45 patients (16 percent); all these patients received more than 1,400 mg/m2. This represents an incidence of 26 percent in patients receiving more than 1,400 mg/m2 of semustine. Two distinct patterns emerged. Abnormal serum creatinine levels developed in two patients while receiving semustine and later progressed to renal failure. Five patients had normal serum creatinine levels throughout their treatment courses but had abnormal creatinine values one month to two years following the completion of drug therapy. Renal failure developed in one of these patients, but the remaining four have had stable renal function for one to two years of additional follow-up. No clinical signs of renal insufficiency were detected in any patients receiving less than 1,400 mg/m2 of semustine. No changes unequivocally attributable to semustine were seen in eight patients at autopsy despite the fact that three had received greater than 1,900 mg/m2 of nitrosourea. This incidence of nephrotoxicity appears to be significantly lower than that previously reported in children. Guidelines for future therapy with semustine are described.

Synthesis and calcium channel-modulating effects of alkyl (or cycloalkyl) 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate racemates and enantiomers.

A group of racemic alkyl (or cycloalkyl) 1,4-dihydro-2,6- dimethyl-3-nitro-4-(2-, 3-, or 4-pyridyl)-5-pyridinecarboxylate isomers (6-14) were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with an alkyl (or cycloalkyl) 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridyl isomers acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle selective calcium channel antagonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers acted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2-pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity where the relative activity profile was cyclopentyl and cyclohexyl > t-Bu, i-Bu, and Et > MeOCH2CH2 > Me. The point of attachment of the C-4 pyridyl substituent was a determinant of GPLA agonist activity where the potency order was generally 4- and 3-pyridyl > 2-pyridyl. (+)-Cyclohexyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridyl)-5- pyridinecarboxylate [(+)-14a] was a less potent calcium antagonist (IC50 = 5.27 x 10(-6) M) than the (-)-enantiomer (IC50 = 7.48 x 10(-8) M) on GPILSM. In the GPLA assay, (+)-14a exhibited a much more potent agonist effect (EC50 = 8.45 x 10(-6) M) relative to the marginal agonist effect produced by (-)-14a. The C-4 2-pyridyl compounds (enantiomers) constitute a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a new drug design concept directed toward the treatment of congestive heart failure, and for use as probes to study the structure-function relationships of calcium channels.

Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates.

A group of racemic alkyl and 2-phenethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3- or 6-substituted-2-pyridyl)-5-pyridinecarboxylates (13a-q) was prepared using a modified Hantzsch reaction that involved the condensation of a 3- or 6-substituted-2-pyridinecarboxaldehyde (7a-j) with an alkyl or 2-phenethyl 3-aminocrotonate (11a-d) and nitroacetone (12). Nuclear Overhauser (NOE) studies indicated there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-dihydropyridine ring, irrespective of whether a substituent is located at the 3- or 6-position. A potential H-bonding interaction between the pyridyl nitrogen free electron pair and the suitably positioned 1,4-dihydropyridine NH moiety may stablize this rotamer orientation. In vitro calcium channel antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. Compounds having an i-Pr ester substituent acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle-selective calcium channel antagonists (GPILSM), except for the C-4 3-nitro-2-pyridyl compound which exhibited an antagonist effect on both GPLA and GPILSM. In contrast, the compounds with a phenethyl ester group, which exhibited antagonist activity (IC50 = 10(-5)-10(-7) M range) on GPILSM, were devoid of cardiac agonist activity on GPLA. Structure-activity relationships showing the effect of a substituent (Me, CF3, Cl, NO2, Ph) at the 3- or 6-position of a C-4 2-pyridyl moiety and a variety of ester substituents (Me, Et, i-Pr, PhCH2CH2-) upon calcium channel modulation are described. Compounds possessing a 3- or 6-substituted-2-pyridyl moiety, in conjuction with an i-Pr ester substituent, are novel 1,4-dihydropyridine calcium channel modulators that offer a new drug design approach directed to the treatment of congestive heart failure and may also be useful as probes to study the structure-function relationships of calcium channels.

Selected anticancer drugs in Phase I trials in the United States (1979--1980).

Phase I trials in 1979 include some drugs representing totally new structures, new schedules of old compounds undergoing reevaluation, and second generation compounds. The rational development of analogs based on structure-activity relationships and on overcoming pharmacologic or toxicologic problems of parent compounds requires much future emphasis; two such examples (pentamethylmelamine and AZQ) are cited here. For all drugs, a plan of clinical development should ensure a more thorough initial evaluation as well as validation of concepts and systems that have prompted their introduction into the clinic. Establishment of clinical usefulness for the new structures, and particularly for three compounds herein reintroduced after a long period of oblivion, would constitute tangible proof of methodological and technological advances that have taken place in the development and clinical evaluation of anticancer drugs.

Management, complications and clinical results of femoral head fractures.

A systematic review of the literature was conducted to investigate data regarding femoral head fractures, particularly focusing on their management, complications and clinical results. Twenty-nine eligible articles, meeting prespecified inclusion criteria, reported on 453 femoral head fractures in 450 patients (mean age of 38.9 years with a mean follow-up of 55.6 months). 84.3% of patients had been victims of an automobile accident. The most widespread classification scheme used was that of Pipkin (65.4% of cases) whereas clinical results were evaluated mainly according to Thompson-Epstein criteria (63.3% of cases). Fracture-dislocations, in their majority, were managed with emergent closed reduction, followed by definite treatment (closed or open), aiming at anatomic restoration of both fracture and joint incongruity. Regarding Pipkin 1 subtype, fractured fragment excision seems to give better results compared to ORIF (p=0.07), while for the more challenging Pipkin 2 fractures the principles of anatomic reduction and stable fixation should be applied. Wound infection was encountered with a rate of 3.2% of surgical cases and sciatic nerve palsy complicated 3.95% of fracture-dislocations. Major late complications included avascular necrosis (11.9%), post-traumatic arthritis (20%) and heterotopic ossification (16.8%). Neither the trochanteric-flip nor the anterior approach seems to put in more danger the femoral head blood supply compared to the posterior one, with the former giving promising long-term functional results and lower incidence of major complication rates.

Vitamin D deficiency in community older adults with falls of gait imbalance: an under-recognized problem in the inner city.

INTRODUCTION: Recent reports suggest that vitamin D deficiency is both under-recognized and undertreated in the geriatric population. In particular, older adults with unexplained pain, falls, and gait disorders often may have osteomalacia from vitamin D deficiency. Currently, older adults are not screened for vitamin D status even when clinical skin suggest deficiency. Our pilot study determined the vitamin D status in older, inner city community adults with features suggestive of vitamin D deficiency. METHODS: The study was prospective and observational. Community-dwelling adults (> 60 years) from our ambulatory clinic or in-patient geriatric program, with features compatible with vitamin D deficiency (history of falls, gait imbalance, unexplained musculoskeletal pain, and/or fractures), were enrolled. IRB approval and signed informed consents were obtained. Following a history and physical exam, blood samples for vitamin D assay and routine chemistries were obtained. Additional information was collected on age, gender, race, dairy product intake, calcium and/or vitamin D supplement use, weekly sunlight exposure, season of exam (May-October vs. November-April), prior falls and fractures, musculoskeletal pain, and gait disturbances. RESULTS: Data were obtained from 48 patients (32F and 16M), mean age of 79 +/- 9 (SD) years (range 60-95). Seventy-seven percent of enrollees had gait disturbances, 77% had a history of falls, 29% had previous fractures and 6% had unexplained pain; 79% consumed milk daily, 25% took calcium supplements and 21% used vitamin D supplements (in a multivitamin or calcium supplement). Self-reported weekly exposure to sunlight ranged from 0 to 42 hours (clothing amount was highly variable). Fifty-four percent of this sample had sub-normal vitamin D status (serum vitamin D < 20 ng/mL). Patient age (P = 0.2287), gender (P=0.9270), exposure to sunlight (P=0.3493), season (P=0.573), and dairy intake (P = 0.735) were not associated with vitamin D status. However, 80% of vitamin D supplement users versus 37% of non-users had normal vitamin D status (P = 0.029) and 75% of calcium supplement users versus 36% of non-users had normal vitamin D status (P = 0.042). A logistic regression model determined that the use of vitamin D or calcium supplements decreased the risk of low vitamin D status by 94% and 93% (P = 0.009 and P = 0.010, respectively). CONCLUSION: In this pilot study of older adults with gait imbalance and falls, vitamin D deficiency (< 20 ng/mL) was observed in 54% of patients tested and previously unrecognized. Higher serum vitamin D levels appeared related to the use of vitamin D (in multivitamin or calcium supplements) suggesting that deficiency may be preventable and easily treated. As vitamin D deficiency is associated with substantial disability, the need for increased awareness to screen and prevent this disorder is evident.

Synthesis and calcium channel antagonist activity of 3-arylmethyl 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates.

Unsymmetrical aryl(heteroaryl)methyl isopropyl ester analogues of nifedipine, in which the 2-nitrophenyl group at C-4 is replaced by a 2- or 3-pyridyl substituent, were synthesized and evaluated as calcium-channel antagonists using guinea pig ileal longitudinal smooth muscle. The point of attachment of the C-4 pyridyl substituent was a determinant of activity where the relative potency order was 2-pyridyl greater than 3-pyridyl. Within the C-4 2-pyridyl series of compounds, and electronegative substituent such as a trifluoromethyl or bromo at the 4 position of the benzyl ester substituent or a nitrogen atom at the 1 position of a 4-pyridylmethyl ester substituent, enhanced activity relative to the unsubstituted benzyl ester analogue. In contrast, in the C-4 3-pyridyl class of compounds, a variety of aryl(heteroaryl)methyl ester substituents did not alter potency to any significant extent. A number of compounds in the C-4 2-pyridyl series possessing 4-pyridylmethyl, 4-trifluoromethylbenzyl, 4-bromobenzyl, and 3-pyridylmethyl ester substituents were approximately equipotent to nifedipine. The aryl(heteroaryl)methyl ester and C-4 2-pyridyl substituents therefore appear to provide important interdependent contributions to calcium-channel antagonist activity.

Synthesis and calcium channel antagonist activity of nifedipine analogues containing 4-pyridyl and 3-arylethyloxycarbonyl substituents.

A series of unsymmetrical 3-arylethyl 5-isopropyl ester analogues of nifedipine, in which the 2'-nitrophenyl group at the 4 position is replaced by 2'- or 3'-pyridyl, were prepared and evaluated as calcium channel antagonists. The point of attachment of the pyridyl substituent was a determinant of activity, 2'-pyridyl analogues always being more potent than corresponding 3'-pyridyl analogues. The introduction of a substituent at the para-position of the phenethyl group in 3-phenethyl ester analogues usually enhanced the activity. The most potent compound was 3-(4'-bromophenethyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2'-pyridyl)-3,5-pyridinedicarboxylate. It was 82-fold more potent than nifedipine, and it did not exhibit a negative inotropic effect on guinea pig left atrium. Desirable features in 1,4-dihydropyridine calcium antagonists of the unsymmetrical 3,5-diester type are therefore a 4-(2-pyridyl) substituent in conjunction with a hydrophobic 3-(4-substituted-phenethyl) ester substituent. The arylethyl ester and the 4-(2'-pyridyl) substituents appear to provide important interdependent contributions to the calcium channel antagonist activity.

Synthesis and calcium channel antagonist activity of alkyl cycloalkyl esters of nifedipine containing pyridinyl substituents.

Alkyl cycloalkyl esters of nifedipine (1a) analogues, in which the ortho-nitrophenyl group at position 4 is replaced by pyridinyl (5-19) were synthesized and evaluated as calcium channel antagonists using the muscarinic receptor-mediated Ca(2+)-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activity profile for unsymmetrical esters (5-15), which indicated the effect of cycloalkyl ring size on activity, was cyclopentyl > cyclohexyl > cyclobutyl. In addition unsymmetrical esters, possessing one R2-cyclohexyl substituent, exhibited an activity profile dependent upon the nature of the R1-alkyl ester substituent with Me > Et, i-Pr, i-Bu > cyclohexyl > t-Bu. The point of attachment of the C-4 pyridinyl substituent was also a determinant of activity for unsymmetrical compounds (R1 = Me, i-Pr; R2 = cyclohexyl, cyclobutyl) where the relative potency order was 2-pyridinyl > 3-pyridinyl > 4-pyridinyl. In contrast, when the R1 and R2-substituents are larger in size (R1 = R2 = cyclohexyl or R1 = i-Pr, R2 = cyclopentyl) the relative activity profile was 3-pyridinyl = 4-pyridinyl > 2-pyridinyl. The C-3 and C-5 ester substituents therefore appear to provide important interdependent contributions to calcium channel antagonist activity, and hence to interaction with the 1,4-dihydropyridine receptor site.