The Internal Medicine Subinternship--Now More Important than Ever: A Joint CDIM-APDIM Position Paper.

For decades, the internal medicine (IM) subinternship has served as a critical interface between undergraduate and graduate medical education. As such, the vast majority of U.S. medical schools offer this rotation to help students prepare for post-graduate training. Historically an experiential rotation, a formal curriculum with specific learning objectives was eventually developed for this course in 2002. Since then, graduate medical education (GME) has changed significantly with the regulation of duty hours, adoption of competency-based education, and development of training milestones and entrustable professional activities. In response to these and many other changes to residency training and medical practice, in 2010, the Association of Program Directors in Internal Medicine (APDIM) surveyed its members-with input from the Clerkship Directors in Internal Medicine (CDIM) Subinternship Task Force-to determine which core skills program directors expected from new medical school graduates. The results of that survey helped to inform a joint CDIM-APDIM committee's decision to re-evaluate the goals of the IM subinternship in an effort to enhance the transition from medical school to residency. This joint committee defined the minimum expectations of what constitutes an IM subinternship rotation, proposed recommended skills for IM subinterns, and discussed challenges and future directions for this crucial course.

Yersinia enterocolitica endocarditis.

A patient with Yersinia enterocolitica endocarditis was seen with bacteremia, valvular vegetation, new heart murmur, and septic embolism. To our knowledge, this is the first reported case of Y enterocolitica infectious endocarditis and is yet another clinical manifestation of disease produced by this organism.

Intrafamilial heterogeneity in hereditary motor neuron disease.

Although there are varied inheritance patterns in motor neuron disease (MND), the phenotype of MND is reported to be constant within these families, ie, cases of amyotrophic lateral sclerosis or primary lateral sclerosis do not occur in pedigrees with cases of spinal muscular atrophy. We describe four pedigrees whose members diverged in the phenotype of MND expressed. The intrafamilial variation of phenotype suggests a similar pathogenesis for some of the varied types of familial MND and the need for careful inquiry of family history in all patients with MND.

Rhenium-186-labeled chimeric antibody NR-LU-13: pharmacokinetics, biodistribution and immunogenicity relative to murine analog NR-LU-10.

A mouse-human chimeric monoclonal antibody (NR-LU-13), with the same pancarcinoma antigen recognition site as a previously studied murine monoclonal antibody (NR-LU-10), was radiolabeled with 186Re using a bifunctional chelate. Nine patients (ages 31-81 yr) with metastatic adenocarcinoma received 186Re NR-LU-13. A single intravenous dose of 42 mg NR-LU-13 labeled with 25 mCi/m2 (two patients) or 60 mCi/m2 (seven patients) was administered. Mean serum disappearance half-time values for the chimeric 186Re NR-LU-10). Fifty percent of the radiolabel was excreted in the urine by 6 days. Tumor localization was demonstrated by gamma camera imaging in seven of nine patients. The percent injected dose per gram in a single tumor biopsy specimen was 0.003% at 72 hr postinjection. Absorbed dose to bone marrow was 1.5 +/- 0.7 rads/mCi and resulted in reversible myelosuppression in five of six evaluable patients who received 60 mCi/m2: median WBC nadir = 2500/microliters; median platelet nadir = 85,500/microliters. Low grade fever, nausea, slight elevations of liver function tests and mild allergic reactions were seen in some patients. The chimeric antibody elicited low levels of anti-NR-LU-13 antibody in six of eight evaluable patients (75%), in contrast to NR-LU-10 which elicited higher levels of human anti-mouse antibody in all patients. This pilot study demonstrates the ability of the chimeric antibody to target tumors with reduced (but not absent) immunogenicity and delayed clearance relative to the murine antibody.

Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunotherapy: results of phase I trials.

Rhenium is a radionuclide with physical and chemical properties suitable for radioimmunotherapy. Two Phase I trials were carried out using 186Re-labeled murine monoclonal antibodies. Patients with refractory metastatic epithelial carcinoma received single doses of either 186Re-labeled intact NR-LU-10, a pancarcinoma antibody, 25-120 mCi/m2 (n = 15) or 186Re-labeled F(ab')2 fragment of NR-CO-02, an anti-CEA variant antibody, 25-200 mCi/m2 (n = 31). Prior to radioimmunotherapy, tumor localization of antibody was confirmed by 99mTc-labeled NR-LU-10 Fab or 99mTc-labeled NR-CO-02 F(ab')2 imaging. Dose-limiting myelosuppression was observed at 120 mCi/m2 following 186Re-NR-LU-10 intact antibody and at 150 mCi/m2 following NR-CO-02 F(ab')2 fragment in heavily pretreated patients. In patients with minimal prior therapy, a maximum tolerated dose for NR-CO-02 F(ab')2 was not reached by 200 mCi/m2. Non-marrow toxicity was minimal. Human anti-mouse antibody developed in all patients receiving intact NR-LU-10, and in 86% patients receiving F(ab')2 NR-CO-02. One patient treated with 186Re NR-CO-02 achieved a partial response. We conclude that 186Re-labeled antibody can be safely administered with significant toxicity limited to marrow.

Inhibition of the inductive activity of demineralized bone matrix by different percutaneous implants.

Teflon tubes with either Gore-Tex (PTFE) or Dacron felt sleeves were implanted percutaneously in rats, in conjunction with demineralized bone matrix. This resulted in different inflammatory reactions, as well as in chondrogenesis and osteogenesis in the subcutaneous tissues. Although induction of osteogenesis by the demineralized bone matrix in the vicinity of the foreign material was inhibited, circumferential bone formation was highly reproducible. The prospect of utilizing demineralized bone matrix in order to enhance acceptance of percutaneous tubes is discussed.

Pericarotid cluster headache.

Cluster headache is generally not associated with recognised disease, and the pathogenesis remains unclear. The onset of typical cluster headaches is reported in a patient with nasopharyngeal carcinoma. The tumor encircled the internal carotid artery but did not extend intracranially. It thus appears possible that cluster headaches may be triggered by processes involving the carotid artery.

Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL): initial phase I/II study results.

Pretargeted radioimmunotherapy (PRIT) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor, and subsequently biotin is then used to target 90Y radioisotope to the tumor localized streptavidin. A chimeric, IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of 186Re in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m2 90Y DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed > 95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi 90Y and the average whole body dose was 0.76 +/- 0.3 cGy/mCi 90Y, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e., five of the seven patients who received 30 or 50 mCi/m2 of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m2 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.

The role of the immune system in the pathogenesis of cancer.

The observation that malignant cells express antigens that may be recognized by immunocytes and that immune effector mechanisms have the capability of destroying tumor cells has increased our appreciation of the biology of cancer and its relationship to immune function as well as offered new options for therapeutic intervention. Clinical trials are in progress to evaluate several different approaches to modifying the host's immune response against tumor. One approach is to administer agents that have direct activity against the malignancy. For example, antibody conjugates bring cytotoxic molecules of chemotherapy, radioisotopes, or toxins directly to the tumor. A second approach is to administer agents that modulate the host's own antitumor response such as IFN-alpha and IFN-gamma. Adoptive cellular immunotherapy aimed at isolating and expanding the host's own tumor-specific lymphocytes and inducing activation and proliferation with lymphokines such as IL-2 has shown encouraging results. Even though clinical data are still quite premature, it is reasonable to assume that in the future immunomodulation including the stimulation of immune effector mechanisms to eradicate tumor, the reconstitution of immune deficiency in diseases such as AIDS, the suppression of immune function to avoid graft rejection and GVHD, and the isolation and insertion of genes encoding tumor antigens into recombinant vectors to immunize the host to the tumor antigen will be commonly and successfully employed.

Enolase catalyzed beta,gamma-alpha,beta isomerization of 2-phospho-3-butenoic acid to (Z)-phosphoenol-alpha-ketobutyrate.

2-Phospho-3-butenoic acid was synthesized and found to be a substrate for both yeast and rabbit muscle enolase (EC 4.2.1.11). Enolase catalyzes the isomerization of 2-phospho-3-butenoic acid to (Z)-phosphoenol-alpha-ketobutyrate, a beta,gamma-alpha,beta isomerization. Nuclear magnetic resonance studies on the product indicate only one isomer is formed. This reaction provides indirect evidence in further support of a carbanion intermediate for the enolase reaction. 2-Phospho-3-butenoic acid is also a good competitive inhibitor of both yeast and rabbit muscle pyruvate kinase (EC 2.7.1.40).

In vivo phosphorylation of the lamin B receptor. Binding of lamin B to its nuclear membrane receptor is affected by phosphorylation.

Previous studies have shown that the nuclear envelope of avian erythrocytes contains a 58-kDa integral membrane protein (p58) which serves as a receptor for the karyoskeletal protein lamin B (Worman, J. H., Yuan, J., Blobel, G., and Georgatos, S. D. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 8531-8534). We now demonstrate that p58 is phosphorylated in vivo at serine residues and that its phosphorylation is stimulated by isoproterenol in a dose-dependent fashion. We further show that dephosphorylation of p58 reduces significantly its binding to lamin B. These data suggest that phosphorylation may constitute one of the major mechanisms regulating the lamina-nuclear membrane interactions.

Subcellular morphological changes in the rat kidney after phosphorus burn.

Experimental phosphorus burns were performed on male rats, in order to evaluate the subcellular changes which had occurred as a result of their lesions. In addition to the external wound caused by the burn itself, pathological changes were observed macroscopically and microscopically in various body organs, mainly the kidneys. These were investigated under the electron microscope for subcellular alterations at their damaged sites, and for biochemical aberrations that were observed in those rats. In the phosphorus-burnt rats the glomeruli were ischemic, showed capillary collapse and exhibited proliferation of mesangial areas and basement membrane thickening. Many necrotic cells were observed in the proximal tubule, where large vacuoles containing myelin-like structures were identified. The lumen of the proximal tubules were completely occluded by cell debris and the cytoplasm was necrotic. Due to the damage caused to the glomeruli, high concentrations of serum urea, serum SGPT and PO-4 were assayed in the phosphorus-burnt rats. These changes may account for the high mortality rate after phosphorus burns and may further understanding of the damage as well as ways of approaching it.

Improving outcomes for persons with aphasia in advanced community-based treatment programs.

BACKGROUND AND PURPOSE: Studies have yet to document that community-based aphasia treatment programs routinely produce results comparable or superior to published research protocols. We explore this issue here in an outcome study of individuals with aphasia enrolled in 2 community-based, comparably managed and equipped therapy programs, which use a specially designed computer-based tool that is employed therapeutically in adherence to an extensive, detailed, and formally trained patient care algorithm. METHODS: Patients (n=60) were assessed before and after treatment with standardized instruments at both the impairment and the disability levels. Pretreatment and posttreatment means were calculated and compared, with statistical significance of differences established with the use of 1-tailed matched t tests. One-way ANOVAs were used to analyze the comparability of patient performance changes among various subgroups, eg, patients in acute versus chronic stages of aphasia, patients by aphasia diagnostic type at start of care, patients by severity level at start of care, and patients by treatment location. RESULTS: Analysis shows that patients spanned a wide range of aphasia diagnostic types, impairment severity levels at start of care, and times after onset. Patients' mean performance scores improved significantly in response to treatment in all measures assessed at both the impairment level and the functional communication level. Mean overall improvements ranged from 6.6% to 19.8%, with statistical significance ranging from P=0.0006 to P<0.0001. ANOVAs revealed no significant differences between improvements in patients in the acute versus chronic stages of aphasia, between those at different impairment severity levels at start of care, between those treated at different locations, or, at the functional level, between those with different diagnostic types of aphasia at start of care. CONCLUSIONS: Measures of both language impairment and functional communication can be broadly, positively, and significantly influenced by therapy services that are delivered to persons with aphasia in these community-based programs. The significant improvements are shown to be available to individuals with chronic as well as acute aphasia and independent of diagnostic type of aphasia, impairment severity at start of care, or geographic program location.

The evolution of the Fenway Community Health model.

Fenway Community Health was founded by community activists in 1971 in the Fenway neighborhood of Boston, Mass, and within a decade had rapidly expanded its medical services for gay men in response to the AIDS epidemic. Increased expertise and cultural competence in lesbian, gay, bisexual, and transgender (LGBT) care led to expansion of medical services to address broader community concerns, ranging from substance use to parenting issues to domestic and homophobic violence, as well as specialized programs for lesbians, bisexuals, and transgendered individuals. Fenway began as a grassroots neighborhood clinic. In 1975, the center recorded 5000 patient care visits; in 2000, Fenway's clinical departments recorded 50,850 visits by 8361 individuals, including more than 1100 individuals receiving HIV-associated care. The center now has more than 170 staff people responsible for clinical programs, community education, research, administration, planning, and development. Over the past few years, Fenway's annual budget has exceeded $10 million. Fenway has established standards for improved cultural competence about LGBT health issues for other health providers and has developed programs to educate the general community about specific LGBT health concerns. This health center may provide a model of comprehensive LGBT health services that have a local impact.

Occult cancer in patients with acute pulmonary embolism.

An association between venous thrombosis and cancer was first suggested by Trousseau, and has been confirmed by multiple postmortem studies. Clinical studies have shown that thrombophlebitis migrans may occur before malignancies become clinically evident, and therefore serves as a clue to occult cancer. A relation between occult cancer and the commoner deep venous thrombosis and pulmonary embolism has not been established. We ascertained the incidence of cancer before and after pulmonary embolism was diagnosed by pulmonary angiography in 128 patients. The incidence of cancer before pulmonary embolism (12%) was essentially the same as that in a comparison group of patients without pulmonary embolism (10%). In the 2 years after pulmonary angiography, however, cancer was diagnosed in 13 patients with pulmonary embolism in contrast to no patients in the comparison group (p less than 0.001). The most frequent cancers involved the lung, gastrointestinal tract, breast, and uterus. The malignancies were nearly always occult when pulmonary embolism occurred. These findings indicate that pulmonary embolism with or without overt deep venous thrombosis should alert the clinician to consider occult cancer.