The FDA's new procedures for the use of investigational drugs in treatment

The Food and Drug Administration has established new procedures to make promising investigational drugs available for treatment of patients with immediately life-threatening or serious diseases as early in the drug development process as possible and well before general marketing begins. The purpose of this article is to inform the medical community about these new procedures and to facilitate their implementation. Examples of immediately life-threatening and serious diseases are given and the procedures that physicians should use to obtain a drug under the new regulations are described. The treatment use of zidovudine (Retrovir), while still in the investigational phase, is described as a case study. The article also summarizes the Food and Drug Administration's new procedures under which drug sponsors can charge for investigational drugs.     

Role of stereotactic biopsy in the management of transplant patients with intracranial lesions

Appropriate treatment of an intracranial lesion is based upon establishing a definitive diagnosis. CT-stereotactic biopsy procedures are highly accurate, are associated with few complications, and are usually performed only with local anesthesia. Stereotactic biopsy is the preferred method for histologically confirming the nature of an intracranial lesion in the immunocompromised patient. The mortality and morbidity approach 1 per cent, respectively. In the large reported series of stereotactic surgery for biopsy, diagnostic accuracy is over 95 per cent. Stereotactic techniques can also be used to aspirate abscesses or localize abscesses or neoplastic lesions excised by craniotomy.     

The filter properties of the arterial beds of organs in rats.

The frequency properties of arterial beds in organs were studied by temporarily ligating the renal, the gastric, the splenic or the superior mesenteric arteries of rats. Blood-pressure waves of the tail arteries were recorded before and during the ligations, and were analysed by Fourier's transformation. Their frequency spectra have been found to change profiles following specific patterns with the ligations of different arteries. The results were significant with regard to the frequency selectivities of the organic arterial beds. Such frequency properties can be clearly explained when the circulation system is viewed as an electrical circuit network in which the organic arterial beds work as filters.     

Iron deficiency anemia in children with exstrophy of the cloaca.

The clinical records of twenty-five children with exstrophy of the cloaca (EC) were retrospectively reviewed to evaluate the prevalence and the clinical characteristics of iron deficiency anemia (IDA). Five of the 25 children with EC (20 %) exhibited IDA at some point. Their ages at the time of diagnosis were between 1.9 and 13.0 years. In the four cases where IDA was thought to be related to iron malabsorption secondary to short-bowel syndrome, its treatment required longer periods of iron supplementation to correct the anemia and to restore the total body iron stores. Physicians caring for children with EC should monitor for and treat IDA as part of a comprehensive management plan.     

Expression profiling of metalloproteinases and inhibitors in cartilage

Objective   To profile the expression of all known members of the matrix metalloproteinase ( MMP ), a disintegrin and metalloproteinase with thrombospondin motifs ( ADAMTS ), and tissue inhibitor of metalloproteinases ( TIMP s) gene families in normal cartilage and that from patients with osteoarthritis (OA).
Methods   Human cartilage was obtained from femoral heads at joint replacement for either osteoarthritis or following fracture to the neck of femur. Total RNA was purified and expression of genes assayed using quantitative real-time PCR.
Results   Several members of the above gene families were regulated in OA. Genes increasing in expression in OA were: at P  < 0.001, MMP-13 , MMP-28 , ADAMTS-16 ; at P  < 0.01, MMP-9 , MMP-16 , ADAMTS-2 , ADAMTS-14 and at P  < 0.05, MMP-2 , TIMP-3 , ADAMTS-12 . Genes decreasing in expression in OA were: at P  < 0.001, MMP-1 , MMP-3 , ADAMTS-1 ; at P  < 0.01, MMP-10 , TIMP-1 , ADAMTS-9 and at P  < 0.05, TIMP-4 , ADAMTS-5 , ADAMTS-15 . Correlation analysis revealed that groups of genes across the gene families are co-expressed in cartilage.
Conclusion   This is the first comprehensive expression profile of all known MMP , ADAMTS and TIMP genes in cartilage. Patterns of expression provide a foundation on which to understand mechanisms of gene regulation in OA and potentially for refining the specificity of anti-proteolytic therapies.     

Ano-cutaneous flap repair for complex and recurrent supra-sphincteric anal fistula.

BACKGROUND: Suprasphincteric fistulae remain the most difficult to cure. OBJECTIVES: The purpose of this study was to evaluate the healing rate of suprasphincteric anal fistula treated by ano-cutaneous advancement flap repair, and the impact of this procedure on continence and quality of life. METHOD: Sixteen patients with complex, recurrent or chronic suprasphincteric fistulae associated with significant tissue damage (necrotizing fasciitis, keyhole deformity and anal stenosis) or who had failed previous surgical procedures were treated by ano-cutaneous flap closure. They were assessed pre and postoperatively by the treating surgeon for wound healing and fistula recurrence and later followed up by phone interview using the St Mark's Hospital incontinence score and the Perianal Disease Activity Index (PDAI) as indicators of treatment outcome. RESULTS: Fifteen patients had successful healing of their fistula with the cutaneous flap, with recurrence in only one. The most common short-term complications were minor graft site wound separation, which healed in all cases without intervention, and wound pain, which settled over time and was not associated with recurrence. Continence improved for almost 70% of the patients, with a significant reduction in St Mark's incontinence scores (t = 2.62, 15 d.f., P = 0.02). PDAI also decreased significantly (t = 7.55, 15 d.f., P < 0.001), demonstrating improvement in quality of life for most patients. CONCLUSION: Ano-cutaneous flap can achieve healing of complex and recurrent suprasphincteric anal fistula in patients who had previously failed at other forms of treatment thus improving their quality of life and continence.     

Use of health care services for psychological distress by immigrants in an urban multicultural milieu.

OBJECTIVE: Research in the United States tends to attribute low rates of use of mental health services by immigrants to economic barriers. The purpose of our study was to examine this issue in the context of Canada's universal health care system. METHODS: A survey of the catchment area of a comprehensive clinic in Montreal interviewed random samples of 924 Canadian-born individuals and 776 immigrants born in the Caribbean (n = 264), Vietnam (n = 234), or the Philippines (n = 278) to assess their health care use for somatic symptoms, psychological distress, and recent life events. RESULTS: Overall rates of use of medical services in the past year were similar in immigrant (78.5%) and nonimmigrant (76.5%) groups. Rates of use of health care services for psychological distress were significantly lower among immigrants (5.5% compared with 14.7%, P < 0.001). This difference was attributable both to a lower rate of use of specialty mental health services by immigrants (2.5% compared with 11.7%, P < 0.001) and to differential use of medical services for psychological distress (3.5% compared with 5.8%, P = 0.02). When level of psychological distress was controlled, Vietnamese and Filipino immigrants were one-third as likely as Canadian-born residents to make use of mental health services. The lower rate of use by immigrants could not be explained by differences in sociodemographics, somatic or psychological symptoms, length of stay in Canada, or use of alternative sources of help. CONCLUSION: Immigrant status is associated with lower rates of use of mental health services, even with universal health insurance. This lower rate of use likely reflects cultural and linguistic barriers to care.     

Immunosuppression: evolution in practice and trends, 1993–2003

Immunosuppression trends for solid organ transplantation have undergone a perceptible shift over the past decade. This period is of interest because it was during this time that the Food and Drug Administration (FDA) expanded the variety of medications to allow for alternatives in immunosuppressive management. An organ-by-organ review of SRTR data identifies several important trends. Antibody induction continues to be used for the majority of kidney (70%) , simultaneous pancreas-kidney (SPK, 79%) pancreas after kidney (PAK, 74%), and intestine recipients (74%). It is used for under half of thoracic organ recipients and remains uncommon for liver transplant recipients (20%). The type of antibody preparation utilized has shifted from muromonab-CD3 and horse ATG to rabbit ATG and monoclonal anti-IL-2 receptor antagonists. Calcineurin inhibitors continue to be used for maintenance immunosuppression for most recipients, although there has been a shift from cyclosporine to tacrolimus. A clear transition is apparent in the choice of antimetabolite from azathioprine to mycophenolate mofetil. Although corticosteroids continue to be used as maintenance immunosuppression for most recipients prior to discharge, there is evidence that efforts of steroid avoidance protocols are having an impact across all organs, as slight decreases in their use have been observed.