Increasing lifestyle physical activity in patients with depression or other serious mental illness

People with severe and persistent mental illness are more likely to be overweight and to suffer from obesity-related illnesses such as diabetes and heart disease than healthy individuals. Lifestyle change interventions that emphasize integrating physical activity into daily life have not been studied extensively in people with mental illness. The authors present the results of an initial feasibility study of a lifestyle modification program for individuals with serious mental illness. Thirty-nine individuals with depression or other serious mental illness were recruited from three different mental health facilities to attend an 18-week lifestyle intervention program promoting physical activity and healthy eating. At each session, participants discussed topics related to healthy lifestyle changes and participated in group walks. Data were collected at baseline, 6 weeks, and 18 weeks. The results demonstrated that individuals who have depression and other serious mental illnesses can participate in a lifestyle intervention program. Participants who attended the final follow-up session had lost weight over the course of the intervention. Study retention was a problem. However, the cost of this type of group-based lifestyle intervention was relatively low, so that such an intervention for this high-risk group may still be cost-effective.     

A Longitudinal Study Of Children With Developmental Language Delay At Age Three: Later Intelligence, Reading And Behaviour Problems

A large sample of Dunedin (New Zealand) children were assessed at age three to identify those with language delay. 2.6 per cent were defined as delayed in verbal comprehension only, 2.3 per cent as delayed in verbal expression only, and 2.3 per cent as delayed in both ('general language delay'). Most of these children, and the remainder of the sample, were assessed for intelligence, reading and behaviour problems at ages seven, nine and 11. Those in every language-delay group had significantly lower mean IQs and lower mean reading scores than the remainder of the sample. They also more often had a low IQ or a lower reading score at ages seven and nine and a lower Verbal and Full-scale IQ at 11. The groups with delayed verbal comprehension and general language delay had significantly more behaviour problems than the remainder of the sample. The group with general language delay was consistently the most disadvantaged in later intelligence, reading and behaviour. Two of the language-delay groups (comprehension and general language) had significantly higher scores on a family disadvantage index. The results of this study confirm the importance of early language delay as a predictor of lower than average intelligence and reading ability and increased behaviour problems.     

Azithromycin prevents recurrence of severe trichiasis following trichiasis surgery: STAR trial

PURPOSE: Trichiasis, the potentially visually disabling result of chronic trachoma, is a leading cause of blindness world wide. Surgery can repair trichiasis, but recurrence of severe trichiasis (lashes touching the cornea) following surgery is likely to have immediate vision threatening consequences. Azithromycin use post-surgery appeared to be beneficial against recurrences but there were a mix of severe, moderate, and mild trichiasis; the specific effect on prevention of severe, vision-threatening recurrence is unknown. This randomized, clinical trial determined if treating trichiasis surgical patients with oral azithromycin compared to usual care (topical tetracycline) resulted in a reduction in severe recurrence of trichiasis to one year. METHODS: In a rural, trachoma hyperendemic district in Ethiopia, 1452 trichiasis patients age 18 or older presenting for surgery were randomly allocated to azithromycin, single 1 gram dose, versus topical tetracycline twice per day for six weeks. The outcome was recurrent severe trichiasis, defined as lashes touching the cornea, or more than 5 lashes touching the globe, to one year. RESULTS: Patients randomized to receive azithromycin had significantly fewer severe recurrences, 4.2/100 person years overall, compared to those randomized to topical tetracycline, 7.9/100 person years (p < 0.01). CONCLUSIONS: A single dose of azithromycin has been shown to reduce severe post-surgical trichiasis recurrence rates to one year and should become standard post surgical treatment.     

Endogenous vasopressin and baroreflex mechanisms

This article reviews the anatomical and functional evidence for ascending pathways from specific brain regions to the PVN and SON which could influence AVP release. The majority of evidence favours the main projection being from a region in the caudal VLM which may coincide with the noradrenergic neurons of the A₁ cell group. However, the transmitter(s) involved have yet to be identified, and whether the pathway is excitatory and/or inhibitory remains to be fully resolved.Anatomical and functional evidence is reviewed for descending projections from the SON and PVN to specific brain regions involved in cardiovascular control, and their possible involvement in baroreflex mechanisms is discussed. However, there is little unequivocal evidence that AVP is the main neurotransmitter utilized by descending projections from PVN to NTS and DMX. While, in some situations, circulating endogenous AVP exerts cardiovascular effects, details of its putative influences on baroreflex mechanisms are lacking.     

Efficacy of biological agents in metastatic triple-negative breast cancer

Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis is poor, and there is no specific target therapy but biological agents combined with chemotherapy may be effective.     

An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications

We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177–labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer.

Small organic ligands which selectively bind with high affinity to tumor-associated antigens are increasingly applied as targeting delivery vehicles of small payloads such as radionuclides (1, 2), drugs (3–5), and fluorophores (6, 7) to tumor sites. In principle, the use of small ligands for targeting applications offers several advantages compared to intact immunoglobulins, including superior penetration of solid neoplastic lesions (8), lower immunogenicity (9), and a reduced cost of goods (10). Low molecular weight compounds may reach their target in vivo in a matter of seconds, thanks to rapid extravasation after intravenous administration (8). A strikingly selective accumulation of small ligands in neoplastic masses has been demonstrated for a small number of targets including somatostatin receptor type 2 (SSTR-2) (11), prostate-specific membrane antigen (PSMA) (12), and carbonic anhydrase IX (CAIX) (13), for which high-affinity small organic ligands are available. Those ligands are typically specific for defined tumor entities, such as neuroendocrine tumors (11), prostate cancer (3), and clear cell renal cell carcinoma (2).¹⁷⁷Lu-DOTATATE (Lutathera), a small-molecule product targeting SSTR-2, has been approved based on phase III data in which a clinically meaningful 82% reduction in the risk of disease progression or death was demonstrated in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (14). Similar data are expected from the currently ongoing phase III VISION trial for ¹⁷⁷Lu-PSMA-617 (clinical trial no. {"type":"clinical-trial","attrs":{"text":"NCT03511664","term_id":"NCT03511664"}}NCT03511664), a radiolabeled small molecule that binds with high affinity to PSMA and that enables targeted beta particle therapy in metastatic castration-resistant prostate cancer patients (15). PHC-102, a ^99mTc-labeled small-molecule derivative targeting CAIX, exhibited favorable uptake in primary and metastatic lesions in patients with renal cell carcinoma (RCC) (2). In light of the promising performance of small organic ligands, it would be desirable to discover and develop small molecules with a broader tumor-targeting potential, therefore covering multiple cancer types.Fibroblast activation protein (FAP) is a type II integral membrane serine protease which is abundantly expressed in the stroma of more than 90% of the epithelial cancers, including malignant breast, colorectal, skin, prostate, and pancreatic cancers (16, 17), while exhibiting a restricted expression in normal adult tissues (18, 19). Haberkorn and coworkers (1, 20, 21) have recently described a series of FAP ligands capable of selective accumulation in FAP-positive tumors in mice and in patients. One of these products (named FAPI-04) showed impressive tumor to background ratios at early time points (i.e., few hours after administration) in a broad range of different cancer types in patients. More than 28 tumor types including breast, lung, pancreatic, head and neck, esophagus, and colorectal cancer presented a remarkably high uptake of a FAP-targeted small molecule labeled with gallium-68 (1, 20, 21). For this reason, FAP has recently been dubbed as “the next billion-dollar target for theranostic products” (22).Here, we describe how the chemical modification of a quinoline moiety in position 8 led to the discovery of OncoFAP, a small organic FAP ligand with a dissociation constant in the subnanomolar concentration range. OncoFAP exhibited a strikingly selective and efficient tumor-targeting performance when equipped with various types of payloads, including radionuclides, fluorophores, and cytotoxic drugs. The targeting delivery of radionuclides to solid tumors is rapidly gaining in popularity, as it may open theranostic opportunities, associated with the use of gallium-68 for positron emission tomography (PET) imaging and of lutetium-177 for therapeutic applications (23). The delivery of fluorescein to tumors enables the conditional activation of chimeric antigen receptor (CAR) T cells, which display a potent biocidal activity only in the presence of fluorescein-labeled adaptor molecules specific to a tumor antigen (24, 25). Finally, small-molecule–drug conjugates (SMDCs) promise to represent a valid alternative to antibody–drug conjugates for cancer therapy, with better tumor penetration and a lower cost of goods (8, 26, 27).     

Follicular dendritic cell tumor: an aggressive head and neck tumor

OBJECTIVE: To characterize the clinicopathologic features of head and neck follicular dendritic cell (FDC) tumor and report the experience of this entity at our institution. Study Design: Two case presentations are compared with a retrospective analysis of all published head and neck cases. SETTING: A tertiary academic medical center. RESULTS: Thirty four cases of FDC tumor of the head and neck cases have been published. Twenty five occurred in the cervical lymph nodes, 4 in the tonsils, 2 in the palate, 1 in the pharynx, 1 in the parapharyngeal region, and 1 in the thyroid gland. Patient ages ranged from 13 to 73 years (mean, 38), and there was a roughly equal number of men and women. Patients were treated with surgery (17), surgery and chemotherapy (8), and surgery and radiation (9). After the primary treatment, 12 patients had no evidence of disease, whereas 5 were incurable. Ten tumors recurred locally and 3 distally. Of these 13 patients who suffered recurrences, 4 had no evidence of disease after secondary treatment, 6 were alive with disease, and one was lost to follow up. Two patients died after recurrence. We add 2 unique cases to the 9 previously reported extranodal cases, 1 in the tonsil and 1 in the parotid gland. CONCLUSION: FDC tumor is a rare malignant neoplasm that can present in the head and neck region in both lymph nodes and extranodal sites. Because of their rarity, these tumors are probably underrecognized by both clinicians and pathologists. Distinct light microscopic, immunohistochemical, and ultrastructural features do exist, however, and are reviewed. Surgery has been the mainstay of treatment and should include diligent control of surgical margins. The role of adjuvant therapy remains controversial. Although originally considered to be a low-grade malignancy, our review suggests both high recurrence rates and metastatic potential. We believe that FDC tumor should be viewed and treated as a moderately aggressive head and neck tumor.     

A comprehensive guide to patient-focused management strategies for Crohn disease.

In Crohn disease, a vigorous inflammatory cascade is caused by the overactivation of helper T-cells in the gastrointestinal system. The results of this inflammation manifest themselves as the symptoms of Crohn disease. This article describes the pathophysiology of Crohn disease as well as multiple pharmacologic and nonpharmacologic interventions that may assist patients with Crohn disease in preventing exacerbations and maintaining longer remissions.