Chronic opioid use: a risk factor for central sleep apnoea and successful therapy with adaptive pressure support servo-ventilation.

Sleep apnoea is a global health problem with significant morbidity. Obesity is a well-known risk factor for this condition, however chronic intake of opioids as a risk factor for central sleep apnoea is under-recognised. We report a case of a 47-year-old man who developed significant sleep-disordered breathing secondary to opioid use for chronic pain. A sleep study demonstrated a picture of complex sleep apnoea with a prominent central sleep apnoea component. He had no significant improvement with conventional continuous positive airway pressure therapy. However, adaptive servo-ventilation had a dramatic effect on his symptoms and compliance. This case highlights the significant risk of central sleep apnoea with opioid use and illustrates the importance of adaptive servo-ventilation in the management of sleep-disordered breathing secondary to impaired central respiratory drive.

Speaking and interruptions during primary care office visits.

BACKGROUND: Patients and physicians value effective communication and consider it an essential part of the medical encounter. This study examined physician-patient communication patterns, and interruptions in communication, during patient visits with family practice and internal medicine residents. METHODS: Observational data obtained from 60 routine primary care office visits included the time that resident physicians and patients spoke and the number and types of interruptions. A total of 22 family practice and internal medicine residents participated, 9 from family practice and 13 from internal medicine. RESULTS: Patients spoke, uninterrupted, an average of 12 seconds after the resident entered the room. One fourth of the time, residents interrupted patients before they finished speaking. Residents averaged interrupting patients twice during a visit. The time with patients averaged 11 minutes, with the patient speaking for about 4 minutes. Computer use during the office visit accounted for more interruptions than beepers. Verbal interruptions, a knock on the door, beeper interruptions, and computer use all interfered with communication, and increased frequency of interruptions are associated with less favorable patient perceptions of the office visit. Female residents interrupted their patients less often than did male physicians. All residents interrupted female patients more often than male patients. Early and increased interruptions were associated with patients' perception that they should have talked more. Third-year residents interrupted patients less frequently than did first-year residents. CONCLUSIONS: Numerous interruptions occurred during office visits. Gender was associated with the pattern of interruptions. Physicians frequently interrupted patients before the patients were finished speaking. Computer use also interrupted physician-patient communication.

Hepatocellular carcinoma in Nigerian children.

Childhood primary hepatocellular carcinoma is rare and accounts for less than 1% of all abdominal malignancies in children < or = 14 years of age. A review of the records of the Cancer Registry, Ibadan, Nigeria covering the period 1960-1995 was scrutinised and 19 cases of hepatocellular carcinoma (HCC) were registered, accounting for 0.49% of all abdominal malignancies over the period of review. The mean (SD) age at presentation was 10.4 (3.0) years and the duration of illness before presentation was short. All the children presented late with abdominal distension and hepatomegaly as the major clinical features. Weight loss was evident in 80% of cases, splenomegaly occurred in 50% and jaundice was present in a third of them. The prognosis was poor; all the cases died within 2 weeks of presentation in hospital. There was evidence to suggest an association between hepatitis B virus infection and HCC in all the liver tissue stained by Shikata-Orcein. This review shows that HCC, though uncommon, is important enough to be considered a possible cause of unexplained hepatomegaly in Nigerian children and that hepatitis B virus is an important aetiological factor. Though the number of cases under review is small, universal early vaccination against hepatitis B virus is necessary in Nigerian children in order to reduce the burden of chronic hepatitis B disease and hepatocellular carcinoma.

A di-leucine sequence and a cluster of acidic amino acids are required for dynamic retention in the endosomal recycling compartment of fibroblasts.

Insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase, is dynamically retained within the endosomal compartment of fibroblasts. The characteristics of this dynamic retention are rapid internalization from the plasma membrane and slow recycling back to the cell surface. These specialized trafficking kinetics result in <15% of IRAP on the cell surface at steady state, compared with 35% of the transferrin receptor, another transmembrane protein that traffics between endosomes and the cell surface. Here we demonstrate that a 29-amino acid region of IRAP's cytoplasmic domain (residues 56--84) is necessary and sufficient to promote trafficking characteristic of IRAP. A di-leucine sequence and a cluster of acidic amino acids within this region are essential elements of the motif that slows IRAP recycling. Rapid internalization requires any two of three distinct motifs: M(15,16), DED(64--66), and LL(76,77). The DED and LL sequences are part of the motif that regulates recycling, demonstrating that this motif is bifunctional. In this study we used horseradish peroxidase quenching of fluorescence to demonstrate that IRAP is dynamically retained within the transferrin receptor-containing general endosomal recycling compartment. Therefore, our data demonstrate that motifs similar to those that determine targeting among distinct membrane compartments can also regulate the rate of transport of proteins from endosomal compartments. We propose a model for dynamic retention in which IRAP is transported from the general endosomal recycling compartment in specialized, slowly budding recycling vesicles that are distinct from those that mediate rapid recycling back to the surface (e.g., transferrin receptor-containing transport vesicles). It is likely that the dynamic retention of IRAP is an example of a general mechanism for regulating the distribution of proteins between the surface and interior of cells.

Identification of an insulin-responsive, slow endocytic recycling mechanism in Chinese hamster ovary cells.

In adipocytes, the insulin-regulated aminopeptidase (IRAP) is trafficked through the same insulin-regulated recycling pathway as the GLUT4 glucose transporter. We find that a chimera, containing the cytoplasmic domain of IRAP fused to transmembrane and extracellular domains of the transferrin receptor, is slowly recycled and rapidly internalized in Chinese hamster ovary cells. Morphological studies indicate that the chimera is slowly trafficked through the general endosomal recycling compartment rather than being sorted to a specialized recycling pathway. A chimera in which a di-leucine sequence within the cytoplasmic domain of IRAP has been mutated to alanines is rapidly internalized and rapidly recycled, indicating that this di-leucine is required for the slow recycling but not for the rapid internalization. Insulin stimulates a 2-3-fold increase in the recycling of the chimera and only a 1.2-fold increase in the recycling of the transferrin receptor. The effect of insulin on the recycling of the chimera is blocked by wortmannin, a phosphatidylinositol 3'-kinase inhibitor. GTPgammaS (guanosine 5'-3-O-(thio)triphosphate) increases the recycling of the chimera by 50% but has no effect on the recycling of the transferrin receptor. In these studies, we have identified in Chinese hamster ovary cells a novel, slow endocytic recycling mechanism that is regulated by insulin.

Transferrin receptor containing the SDYQRL motif of TGN38 causes a reorganization of the recycling compartment but is not targeted to the TGN.

The SDYQRL motif of the cytoplasmic domain of TGN38 is involved in targeting TGN38 from endosomes to the TGN. To create a system for studying this pathway, we replaced the native transferrin receptor (TR) internalization motif (YTRF) with the SDYQRL TGN-targeting motif. The advantages of using TR as a reporter molecule include the ability to monitor trafficking, in both biochemical and microscopy experiments, using the natural ligand transferrin. When expressed in CHO cells, the SDYQRL-TR construct accumulated in juxtanuclear tubules and vesicles that are in the vicinity of the TGN. The SDYQRL-TR-containing structures, however, do not colocalize with TGN markers (e.g., NBD ceramide), and therefore the SDYQRL motif is not sufficient to target the TR to the TGN. The morphology of the SDYQRL-TR-containing juxtanuclear structures is different from the recycling compartment found in cells expressing the wild-type TR. In addition, the SDYQRL-TR-containing juxtanuclear compartment is more acidic than the recycling compartment in cells expressing the wild-type TR. The juxtanuclear compartment, however, is a bona fide recycling compartment since SDYQRL-TR was recycled back to the cell surface at a rate comparable to the wild-type TR, and sphingomyelin and cellubrevin, both of which label all compartments of the endocytic recycling pathway, colocalize with SDYQRL-TR in the juxtanuclear structures. These findings demonstrate that expression of the SDYQRL-TR construct alters the morphology and pH of endocytic recycling compartments rather than selectively affecting the intracellular trafficking pathway of the SDYQRL-TR construct. Therefore, the SDYQRL trafficking motif is not simply a molecular address that targets proteins to the TGN, but it can play an active role in determining the physical characteristics of endosomal compartments.

Umbilical vein serum amino acid levels in African Americans: relationship to birthweight and maternal variables.

Compared with other racial groups, African-American women show a disproportionately high risk of delivering low birthweight babies. In a retrospective study of African-American infants born at Meharry Hubbard Hospital, which predominantly serves the underprivileged inner-city poor, free amino acid concentrations were measured in umbilical venous serum from infants born following 34 to 42 weeks gestation. Significant reductions in levels of glycine, serine, alanine, the branched-chain amino acids, and the sum of the so-called dispensable amino acids were associated with decreased birthweight. Glycine, a quantitatively important residue in collagen and a component of reduced glutathione (gamma-glutamyl-cysteinyl-glycine), which is featured in the gamma-glutamyl amino acid transport cycle, was most consistently and severely affected. This study not only indicated that selective reduction in transplacental amino acid transport may be an important factor in intrauterine growth retardation in African Americans, but also confirmed the dietary necessity of the structurally simple amino acid glycine during pregnancy.

Adaptation of lactose maldigesters to continued milk intakes.

Twenty-five lactose-maldigesting and lactose-intolerant African Americans, ranging in age from 13 to 39 y, were given gradually increasing amounts of lactose in milk over a period of time until the maximum lactose dose tolerated was determined. Seventeen (77%) of the 22 subjects who completed the study tolerated > or = 12 g lactose and 5 (23%) tolerated < 12 g. Breath-hydrogen tests done on each subject with the maximum dose of lactose tolerated showed that only four (18%) had a breath-hydrogen concentration < 5 ppm above fasting concentration. This study suggests that the majority of African-American young adults who claim intolerance to moderate amounts of milk can ultimately adapt and tolerate > or = 12 g lactose in milk (the equivalent of 8 oz of full-lactose milk) with minimal or no discomfort if milk is ingested in gradually increasing amounts. The mechanism of adaptation is assumed to be an increased tolerance to colonic lactose-fermentation products.

Correlation of lactose maldigestion, lactose intolerance, and milk intolerance.

Lactose digestion and tolerance were evaluated in 164 African Americans ranging in age from 12 to 40 y who claimed intolerance to one cup (240 mL) or less of milk. With use of a breath-hydrogen test with 25 g lactose as test dose and the presence or absence of symptoms, 50% of the subjects were classified as lactose maldigesters and intolerant, 8% were maldigesters but tolerant, 15% were digesters but intolerant, and 27% were digesters and tolerant. Forty-five subjects from the lactose maldigesting and intolerant group were further tested for milk intolerance in a double-blind study. Sixty-seven percent of the subjects reacted appropriately to the presence or absence of lactose in ingested milk whereas 33% reported symptoms to both low-lactose milk and milk containing lactose. The results suggest that the cause of milk intolerance in as many as one-third of African Americans claiming symptoms after ingestion of a moderate amount of milk cannot be its lactose content.

A secretory protein restricted to type I cells in neonatal rat submandibular glands.

The perinatal submandibular gland of the rat contains an 89-kDa secretory protein (Protein C) that is released upon cholinergic stimulation. Polyclonal antibodies raised against Protein C show that this protein is localized in the Type I cells and is not found in typical Type III cells. However, morphological variants of Type III cells (Type IIIP) contain material that is cross-reactive with antibodies to Protein C. Cross-reactive components also are found in mucous cells of the neonatal sublingual glands, parotid and minor sublingual glands, and adult submandibular and sublingual glands. Immunoblots of electrophoretically separated proteins show a distinct Protein C band at 89 kDa only in neonatal submandibular glands; neonatal sublingual and minor sublingual glands show some diffuse reactivity over a range of mobilities encompassing that of Protein C. We propose that the cross-reactive components of mucous cells and Type IIIP cells are not Protein C, but different proteins associated with mucous differentiation, and that the Type IIIP cells of the neonatal submandibular gland are in transition from Type III to mature mucous cells.

Secretory proteins as markers for cellular phenotypes in rat salivary glands.

The neonatal submandibular glands (SMG) of the rat contain two types of cells: Type III cells secrete a group of proteins in response to beta-adrenergic stimulation, and Type I cells secrete a different protein, called Protein C (89 kDa), in response to cholinergic stimuli (Ball and Redman, 1984). Polyclonal antibodies raised to Protein B1 (26 kDa) showed that the several proteins in the B1-Immunoreactive Protein (B1-IP) group are localized exclusively to Type III cells. Although we expected that antibodies to Protein B1 would label only the submandibular gland, we found instead that the serous demilunes of the sublingual gland (SLG) and the acinar cells and intercalated ducts of the parotid gland (PRG) were strongly reactive in both the neonate and the adult. Immunoelectrophoretic analysis of gland extracts showed the major reactive species in the sublingual gland to have different mobilities than the B1-IP. On the other hand, reactive species in the parotid gland had mobilities identical to those of two SMG proteins. In the adult SMG, the neonatal Type I and Type III cells are not present, and the acinar cells are devoid of B1-IP reactivity; however, the cells of the intercalated ducts have components reactive with anti-B1 antibodies, and these do not appear to be identical to any neonatal bands. In contrast to the submandibular gland, the adult parotid and sublingual glands retain the localization of B1-IP reactivity in PRG acinar and intercalated duct cells and in SLG demilunes, and they show the neonatal immunoelectrophoretic pattern. This raises the possibility that the major B1-IP species in the adult PRG may be identical to transient proteins of the neonatal SMG.

Acute illness in Nigerian children with sickle cell anaemia.

The pattern of illness in 60 consecutive children with homozygous sickle cell disease who attended the Paediatric Emergency Room of a busy Lagos hospital with acute illness was studied prospectively. Their ages ranged from 3 months to 13 years with a peak in the 2nd year. There were twice as many boys as girls. The commonest symptoms were fever, limb or abdominal pain and cough, and the commonest signs were pallor and hepatomegaly. Painful crises occurred in 27, anaemic crises in 11, and a combination of these in 12 children. Infection was detected in 76% of subjects in crises. Infection was found in 82% of all the children and was mainly bacterial. The commonest infections were pneumonia (35%), bacteraemia (32%), tonsillitis/pharyngitis (17%) and osteomyelitis (8%). The predominant bacteria isolated were Klebsiella spp (38%), E. coli (23%), Staph. aureus (23%), Staph. albus (23%) and Pseudomonas spp (23%). Some children had multiple isolates. Bacterial infection was a major cause of morbidity in very young children and merits appropriate control and preventive measures in this age group. The spectrum of bacteria isolated makes it unlikely that the specific anti-pneumococcal measures widely advocated in Europe and America for young children with SCA would be appropriate in Nigeria.