Mortality in patients with diabetic neuropathic osteoarthropathy (Charcot foot).

OBJECTIVE: To determine the mortality of a population of patients diagnosed with Charcot neuropathic osteoarthropathy managed by a single specialist unit and to compare the results with a control population. METHODS: We have undertaken a retrospective analysis of all cases of Charcot foot on the comprehensive database which has been maintained at the specialist diabetic foot clinic at the City Hospital, Nottingham since 1982. Survival and the incidence of amputation (major and minor) was compared with a control population referred with uncomplicated neuropathic ulceration. Controls were individually matched for gender, age (+/-2 years), disease type, disease duration (+/-2 years) and year of referral (+/-3 years). RESULTS: Forty-seven cases (21 female, 26 male) of Charcot foot were identified, of whom 18 (38.3%) had Type 1 diabetes. Mean age and disease duration at presentation were 59.2 +/- 13.4 (sd) and 16.2 +/- 11.2 years, compared with 59.7 +/- 12.6 and 16.3 +/- 11.2 years, respectively, in the controls. Twenty-one (44.7%) of those with Charcot had died, after a mean interval of 3.7 +/- 2.8 years. This compared with 16 (34.0%) after a mean 3.1 +/- 2.7 years in the control group. Mean duration of follow-up in the survivors was 4.7 +/- 4.9 years (Charcot) and 5.3 +/- 3.9 years (controls). A total of 11 (23.4%) Charcot patients had had a major amputation on the side of the index lesion, compared with five (10.6%) controls. There was no difference between the two groups (P > 0.05, Chi-square). CONCLUSIONS: The mortality in this group of patients with Charcot foot was higher than expected. Nevertheless, there was no difference between those with Charcot and those with uncomplicated neuropathic ulceration. It is possible that it is neuropathy, rather than Charcot osteoarthropathy, which is independently associated with increased mortality in diabetes. The mechanism underlying any such association is not known. There is a need for a formal, prospective, multicentre study to investigate the life expectancy and cardiovascular risk of those with Charcot osteoarthropathy.     

The mitogenic effect of KGF and the expression of its cell surface receptor on cultured normal and malignant human oral keratinocytes and on contiguous fibroblasts

This study examined the mitogenic response to keratinocyte growth factor (KGF) of normal and tumour-derived human oral keratinocytes in which the degree of cellular differentiation was known and in contiguous fibroblast cultures derived from the malignant epithelial cultures. Keratinocytes, but not fibroblasts, were stimulated by KGF. There by demonstrating epithelial target cell specificity of the ligand. KGF-induced stimulation of the tumour-derived keratinocytes cultured in the absence of the 3T3 fibroblast support broadly correlated with the degree of cellular differentiation; well-differentiated keratinocytes were stimulated more by KGF than their less differentiated counterparts. Malignant oral keratinocytes expressed KGF cell surface receptors (K_D 451-709 pM; receptors/cell 2306-413645), but KGF receptor mRNA did not correlate with either KGF-induced mitogenesis or the degree of epithelial cell differentiation. When the tumour-derived keratinocytes were cultured in the presence of 3T3 fibroblasts, the mitogenic response to KGF was comparable to normal epithelial cells. The results suggest that KGF-mediated growth stimulation may not be significant in providing a selective advantage for the growth of malignant keratinocytes.     

Recent trends of age-specific pneumoconiosis mortality rates in the United States, 1985-1996: coal workers' pneumoconiosis, asbestosis, and silicosis

The authors examined the temporal trends of age-specific pneumoconiosis mortality from coal worker's pneumoconiosis (CWP), asbestosis, and silicosis in the United States in 1985-1996. Mortality data were derived from the National Center for Health Statistics multiple causes of death files for the period. Age-specific mortality rates were computed for three age groups (15-44, 45-64, and > or = 65 years) among decedents with mention of CWP, asbestosis, or silicosis. Linear regression analysis was performed to examine the annual changes in age-specific mortality rates, by age group, with each specific condition. The CWP mortality rates declined significantly (p = 0.0001) in the groups 45 years old and older, but not in the age group 15-44. Asbestosis mortality rates declined significantly (p = 0.005) for the age group 45-64, while increasing (p = 0.0001) for those aged 65 years and older. However, in the younger age group 15-44, the rates showed no significant trend. Silicosis mortality rates declined significantly (p = 0.0001) for all groups. The continued occurrence of deaths from CWP, asbestosis, and silicosis among young adults may be the result of high levels of exposure to occupational risks. These results suggest that pneumoconiosis surveillance may help to evaluate the temporal pneumoconiosis mortality patterns in the United States.     

Bladder cancer arising in a spina bifida patient

We report the case of a 52-year-old patient with spina bifida, neurologic bladder, and a history of recurrent urinary tract infections (UTIs) in whom a bladder cancer was incidentally discovered. Cytology, cystoscopy, and cystography showed nonspecific, extensive inflammatory lesions. Cystography demonstrated a complex of diverticulae and cellules. Pathologic examination of a diverticulectomy specimen revealed a grade III pT3b transitional and squamous cell carcinoma. Because of the similar disease causation (recurrent UTIs, stones, and indwelling catheterization), we suggest extension of the guidelines proposed for patients with spinal cord injuries (ie, annual serial bladder biopsies) to patients with nontraumatic neurogenic bladder.     

Pain and pain management in newborn infants: a survey of physicians and nurses

BACKGROUND: Despite an increased awareness among clinicians regarding pain and pain management for infants undergoing surgery, pain associated with procedures performed outside the operating room may not be adequately managed. PURPOSE: To examine the beliefs and self-described behavior of physicians and nurses regarding the management of procedural pain in newborn infants. METHODS: A survey was distributed to 467 clinicians (nurses and physicians) working in 11 level II and 4 level III nurseries in a large metropolitan area. Respondents were asked to rate the painfulness of 12 common bedside nursery procedures and how often pharmacologic and nonpharmacologic (comfort) measures are currently used and should be used for those procedures. Demographic data were also collected. RESULTS: Surveys were completed by 374 clinicians (80% response rate). Physicians and nurses believe infants feel as much pain as adults and that 9 of the 12 listed procedures are moderately to very painful. Neither pharmacologic nor comfort measures are believed to be used frequently, even for the most painful procedures. Physicians and nurses believe both pharmacologic and comfort measures should be used more frequently, but nurses believe comfort measures should be used more frequently than do physicians. Beliefs about infant pain and procedural pain were related to pain management preferences. Physicians' but not nurses' ratings were associated with significant personal pain. CONCLUSIONS: Despite their beliefs that infants experience significant procedure-related pain, clinicians believe pain management for infants remains below optimal levels. Barriers to more consistent and effective pain management need to be identified and surmounted.     

Bacterial and mammalian DNA alkyltransferases sensitize Escherichia coli to the lethal and mutagenic effects of dibromoalkanes

Here we confirm and extend our previous studies demonstrating that the mutagenic potency of 1,2-dibromoethane (DBE) and dibromomethane (DBM) is markedly enhanced (not prevented) in bacteria expressing the O6- alkylguanine-DNA alkyltransferase (ATase) encoded by the Escherichia coli ogt gene. We demonstrate that, in close parallel with mutagenesis, the Ogt ATase sensitizes the bacteria to the lethal effects of these carcinogens, suggesting that one or more of the potentially mutagenic lesions induced by DBE and DBM in the presence of Ogt has additional lethal capacity. We further demonstrate that the sensitization to both lethality and mutagenesis by DBE and DBM is a property shared by other DNA alkyltransferases. This objective was accomplished by quantifying the induction of mutations and lethal events in ogt- ada- E. coli expressing an exogenous bacterial or mammalian ATase from a multicopy plasmid. Mammalian recombinant ATases enhanced the lethal and mutagenic actions of DBE and suppressed the lack of sensitivity of the vector- transformed bacteria to DBM. In most cases the order of effectiveness of the ATases ranked: murine > human > Ogt > rat. Further comparisons included the full-length Ada ATase from E. coli and a truncated Ada version (T-ada) that retains the O6-methylguanine binding domain of the protein. The full-length Ada ATase was effective in enhancing the lethality but not the mutagenicity induced by DBE and DBM. The T-ada ATase provided less sensitization than Ada to lethality by DBE, but of the three bacterial ATases T-ada yielded the highest sensitization to mutagenesis by this compound. T-ada and Ada ATases were in general less effective than the mammalian versions, with the exception of the rat recombinant ATase. The effectiveness of the different mammalian and bacterial ATases in promoting the deleterious actions of dibromoalkanes was compared with the effectiveness of these proteins in suppressing the lethal and mutagenic effects induced by N-nitroso-N-methylurea. The ability to sensitize E. coli to the lethal and mutagenic effects of DBE and DBM seems restricted to DNA alkyltransferase, since overexpression of thioredoxin (Trx) or glutaredoxin (Grx1) in ogt- ada- cells showed no effect, in spite of the reported potential of bioactive dihaloethane- derived species to alkylate Trx.      

The safety and tolerability of levodopa eye drops for the treatment of ocular disorders: A randomized first‐in‐human study

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first‐in‐human study reports on the safety profile of a novel dopamine‐based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first‐in‐human, monocenter, placebo‐controlled, double‐blind, paired‐eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18–30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [μmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [μmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4‐week trial, and after a 4‐month follow‐up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non‐ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration) in which levodopa has been identified as a potential clinical intervention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data indicate that levodopa/carbidopa eye drops can safely inhibit the development of experimental myopia in animal models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated whether levodopa/carbidopa eye drops are safe and tolerable to the human eye.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In this phase I, first‐in‐human, monocenter, randomized, double‐blind, placebo‐controlled, multidose trial, levodopa/carbidopa eye drops were found to be safe and well tolerated in healthy adult males over a 4‐week period. Furthermore, no non‐ocular adverse events were reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As topical administration of levodopa/carbidopa eye drops is well tolerated in humans, the efficacy of this novel ophthalmic treatment at inhibiting the development of myopia in patient populations can now be assessed. If found to be effective, this will provide a powerful new method for inhibiting the onset and development of the leading cause of low vision worldwide. This topical formulation may also provide a valuable tool in the treatment of other visual disorders shown to be responsive to levodopa therapy (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration).     

双波长薄层扫描法测定痛得安胶囊中新乌头碱的含量

目的：建立痛得安胶囊中新乌头碱的含量测定方法。方法：采用双波长薄层扫描法,以正己烷－乙酸乙酯－无水乙醇－氨水（１２：８：２．５：０．５）为展开剂,碘化饿钾试液为显色剂,测定该制剂中新乌头碱的含量。结果：线性范围为１～６ｕｇ。平均回收率为９４．８０％,ＲＳＤ为２．０３％。结论：本法操作简便。结果可靠。实用,适合该制剂中新乌头碱的含量测定。