Epilogue to the Gerald Maggiora Festschrift: a tribute to an exemplary mentor, colleague, collaborator, and innovator.

In May 2022, JCAMD published a Special Issue in honor of Gerald (Gerry) Maggiora, whose scientific leadership over many decades advanced the fields of computational chemistry and chemoinformatics for drug discovery. Along the way, he has impacted many researchers in both academia and the pharmaceutical industry. In this Epilogue, we explain the origins of the Festschrift and present a series of first-hand vignettes, in approximate chronological sequence, that together paint a picture of this remarkable man. Whether they highlight Gerry's endless curiosity about molecular life sciences or his willingness to challenge conventional wisdom or his generous support of junior colleagues and peers, these colleagues and collaborators are united in their appreciation of his positive influence. These tributes also reflect key trends and themes during the evolution of modern drug discovery, seen through the lens of people who worked with a visionary leader. Junior scientists will find an inspiring roadmap for creative collegiality and collaboration.

Computer-assisted quantitative upper airway analysis following modified uvulopalatal flap and lateral pharyngoplasty for obstructive sleep apnoea: a prospective case-controlled study.

OBJECTIVES: The study aims to perform static and dynamic quantitative assessment of the anatomical changes of the upper airway before and after modified uvulopalatal flap and lateral pharyngoplasty and comparison of the improvement in airway dimensions, collapsibility and extent of normalisation to that of control patients. DESIGN: Prospective case-controlled study. SETTING: Computer-assisted quantitative measurement is used to compare upper airway parameters before and after modified uvulopalatal flap and lateral pharyngoplasty in patients with obstructive sleep apnoea (OSA). PARTICIPANTS: Patients with obstructive sleep apnoea diagnosed on sleep study and failed positive airway pressure therapy. MAIN OUTCOME MEASURES: Sleep study results, upper airway parameters and symptom score following surgery and its comparison to normal patients to assess the degree and extent of normalisation. RESULTS: Thirty-five study and 32 control subjects were recruited and completed the study. All the retropalatal airway dimensions like area, transverse diameter, longitudinal diameter and collapsibility showed statistically significant improvement following surgery. The success rate of this surgery is 43% (15 of 35) overall, 58% (14 of 24) for patients with isolated palatal obstruction and only 9% (1 of 11) for patients with multi-level obstruction. Comparing obstructive sleep apnoea to the control subjects, there are obvious and logical differences in their biostatistics, sleep study parameters and airway dimensions. The postoperative obstructive sleep apnoea retropalatal longitudinal diameter has a higher tendency of normalising to be comparable to those of control patients. CONCLUSIONS: Modified uvulopalatal flap and lateral pharyngoplasty is an effective surgical technique for the treatment of obstructive sleep apnoea. The surgery increases the resting retropalatal dimensions and reduces the retropalatal collapsibility.

Phasic acetylcholine release and the volume transmission hypothesis: time to move on.

Traditional descriptions of the cortical cholinergic input system focused on the diffuse organization of cholinergic projections and the hypothesis that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. The ability of ACh to reach the extrasynaptic space (volume neurotransmission), as opposed to remaining confined to the synaptic cleft (wired neurotransmission), has been considered an integral component of this conceptualization. Recent studies demonstrated that phasic release of ACh, at the scale of seconds, mediates precisely defined cognitive operations. This characteristic of cholinergic neurotransmission is proposed to be of primary importance for understanding cholinergic function and developing treatments for cognitive disorders that result from abnormal cholinergic neurotransmission.

Dizocilpine-induced accuracy deficits in a visual signal detection task are not present following D-cycloserine administration in rats.

The N-methyl-D-aspartate (NMDA) receptor system is thought to be underactive in schizophrenia which may contribute to attentional dysfunction in this disease. In a visual signal detection task that required discrimination of signaled-trials from trials with no signal, the NMDA receptor antagonist, dizocilpine (0.05 mg/kg), increased errors on non-signal trials. Co-administration of dizocilpine and 10.0 mg/kg D-cycloserine, a co-agonist at the glycine site on the NMDA receptor, significantly decreased the error rate on non-signal trials compared to dizocilpine alone. These results suggest that drugs targeting the glycine site may be beneficial for attenuating attentional deficits associated with an underactive NMDA receptor system.

Optimization of electroporation conditions for Mycobacterium avium.

Successful transformation and subsequent genetic manipulation of Mycobacterium avium requires suitable vectors, efficient transformation systems, and reliable selectable markers. A systematic analysis of the parameters involved in the transformation of M. avium was performed to optimize DNA transfer. Factors examined included the composition of the growth medium, growth medium additives, variations in washing of the bacteria prior to electroporation, and conditions of electroporation. Of the parameters assayed, the frequency of transformation (defined as the number of transformants per 10(6) transformed bacteria) showed the greatest increase with the addition of 1.5% glycine to the M. avium culture medium and the use of higher concentrations of plasmid DNA. The addition of 0.5 M sucrose to the growth medium and wash solution yielded a modest increase in transformation frequency, but more importantly afforded greater consistency of results between different batches of cells with no decrease in transformation yields following freezing and thawing. We also confirmed that gfp could be used as a selective marker for M. avium, even as a single copy integrant, and allowed for rapid discrimination between false and true transformants. Using this protocol, we were able to transform nine of 11 clinical strains of M. avium.

Prediction of the tertiary structure of the beta-secretase zymogen.

beta-Secretase, also known as BACE, is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid beta-peptide. The activity of beta-secretase is the rate-limiting step of brain plaques production in vivo, and hence is a potential target for disease modifying drugs for Alzheimer's disease. To better understand the mechanism of action of beta-secretase and help explore novel strategies for drug discovery for Alzheimer's disease, it is important to elucidate the three-dimensional structure of its zymogen. Based on the X-ray structure of the enzyme's protease domain and the X-ray structure of pepsinogen, a model of the three-dimensional structure of the beta-secretase zymogen has been constructed. Comparison of the computed structure of pro-BACE with X-ray structures of pepsinogen and progastricsin (two other pro-aspartyl proteases) reveals a significant difference in the relationship of the pro-segment to the catalytic aspartates. In both pepsinogen and progastricsin a lysine side-chain in the pro-segment forms a salt bridge to the two catalytic aspartates, occupying the position normally occupied by a catalytic water. In the pro-BACE model there is no salt bridge, and the corresponding residue-a proline-does not interact at all with the catalytic residues. These findings can be used to elucidate the recent observations that the pro-domain of beta-secretase does not suppress activity as in a strict zymogen but does appear to facilitate proper folding of an active protease domain. The predicted three-dimensional structure of beta-secretase zymogen and the relevant findings might also provide useful insights for rational design of effective drugs against Alzheimer's disease.

Terazosin for treating symptomatic benign prostatic obstruction: a systematic review of efficacy and adverse effects.

OBJECTIVE: To systematically review and evaluate the effectiveness and adverse effects of the alpha-antagonist, terazosin, for treating urinary symptoms associated with benign prostatic obstruction (BPO). METHODS: Studies were sought and included in the review if they were randomized trials of at least 1 month duration, involved men with symptomatic BPO and compared terazosin with placebo or active controls. The study, patient characteristics and outcome data were extracted in duplicate onto standardized forms using a prospectively developed protocol. RESULTS: Seventeen studies involving 5151 men met the inclusion criteria, i.e. placebo-controlled (10), alpha-blockers (seven), finasteride alone or combined with terazosin and placebo (one), and microwave therapy (one). The study duration was 4-52 weeks; the mean age of the men was 65 years and 82% were white. Baseline urological symptom scale scores and flow rates showed that men had moderate BPO. Efficacy outcomes were rarely reported in a way that allowed for data pooling, but indicated that terazosin improved symptom scores and flow rates more than did placebo or finasteride, and similarly to other alpha-antagonists. The pooled mean percentage improvement for the Boyarsky symptom score was 37% for terazosin and 15% for placebo (four studies). The mean percentage improvement for the American Urological Association symptom score was 38%, compared with 17% and 20% for placebo and finasteride, respectively (two studies). The pooled mean improvement in the International Prostate Symptom Score of 40% was similar to that with tamsulosin (43%). Peak urinary flow rates improved more with terazosin (22%) than with placebo (11%) and finasteride (15%), but did not differ significantly from the other alpha-antagonists. The percentage of men discontinuing terazosin was comparable with those receiving placebo and finasteride, but greater than with other alpha-antagonists. Adverse effects were greater than with placebo and included dizziness, asthenia, headache and postural hypotension. CONCLUSIONS: The available evidence indicates that terazosin improves the symptoms and flow rates associated with BPO; it was more effective than placebo or finasteride and similar to other alpha-antagonists. Adverse effects were generally mild but more frequent than with other alpha-antagonists and associated with a two- to four-fold increase in treatment discontinuation.

Does gymnastics training inhibit growth of females?

OBJECTIVE: The increasingly dominant performance of smaller-sized female gymnasts and increased magnitude of training beginning at an early age have prompted public and medical concerns, especially from an auxological perspective. The objective of this review is to determine if gymnastics training inhibits growth of females. DATA SOURCES: An extensive research of MedLine (PubMed interface) along with cross-referencing was conducted using the Text and MeSH words "gymnastics" in combination with "growth," "maturation," "body height," "body weight," and "growth plate." Our analysis is limited to English articles only. STUDY SELECTION: All published studies that included data related to the research questions were included. MAIN RESULTS: Although data from three historical cohort studies indicate that female gymnasts are short even before they begin training, clinical reports and cohort studies do suggest that some female gymnasts experience attenuated growth during training followed by catch-up growth during periods of reduced training or retirement. There is conflicting evidence whether the "catch-up" is complete. There were no studies reporting prevalence or incidence of inadequate growth. Three cohort studies provide evidence of reduced growth but training was not partitioned from other confounding factors in the gymnastics environment. Although there is a paucity of studies examining the link of dietary practices with diminished growth in female gymnasts, a review of related dietary literature indicates the potential for insufficient energy and nutrient intake among female gymnasts. CONCLUSIONS: Elite level or heavily involved female gymnasts may experience attenuated growth during their years of training and competition followed by catch-up growth during reduced training schedules or the months following retirement. However, a cause-effect relation between gymnastics training and inadequate growth of females has not been demonstrated.

Neurotrophin and neurotrophin receptor expression by cells of the human lamina cribrosa.

PURPOSE: To determine whether cells and tissue from the human lamina cribrosa (LC) express neurotrophin and tyrosine kinase (trk) receptor mRNA and protein and whether these cells secrete neurotrophins. METHODS: Synthesis of cDNA and the reverse transcription-polymerase chain reaction (RT-PCR) were conducted using total RNA obtained from well-characterized cell lines from the human LC and human optic nerve head (ONH) tissue. Immunofluorescent localization and Western blot analysis were used to evaluate neurotrophin and trk protein expression in cells and tissue from the human LC. Immunoassay systems (ELISAs) were used to detect the secretion of neurotrophins. RESULTS: Two morphologically distinct cell types (LC cells and ONH astrocytes) were isolated and characterized from the human LC. Messenger RNA for each of the neurotrophins, three full-length trk receptors and two truncated trk receptors were detected in both cell types and in human ONH tissue. Protein for the neurotrophins and trk receptors were detected in LC cells, ONH astrocytes, and ONH tissue. Neither cell type expressed mRNA or protein for the low-affinity neurotrophin receptor p75. The secretion of neurotrophins was observed in both cell types. CONCLUSIONS: Cells from the human LC express mRNA and protein of neurotrophins and trk receptors. In addition, cells from the LC secrete neurotrophins, which suggests that there is paracrine and/or autocrine signaling within the LC. Neurotrophin signaling within this region of the ONH may play important roles in the maintenance of the normal LC and in such diseases as glaucoma.

Immortalized human corneal epithelial cells for ocular toxicity and inflammation studies.

PURPOSE: To develop a metabolically competent, human immortalized corneal epithelial cell line for use in toxicity and inflammation studies. METHODS: Primary corneal epithelial cells (P-CEPI) were immortalized by a recombinant simian virus (SV)40 T antigen retroviral vector defective for viral replication. The cells were grown in serum-free medium with the addition of bovine pituitary extract, cloned at passage 15 and one of the best-growing clones, CEPI-17-CL4, was extensively characterized for differentiation and metabolic characteristics of the human corneal epithelium. Methods used were immunostaining, reverse transcription-polymerase chain reaction (RT-PCR), northern blot analysis, and enzyme assays. RESULTS: The CEPI-17-CL4 cells showed a typical cobblestone morphology, grew to more than 200 passages and expressed the SV40 T antigen in the nucleus of every cell. Immunofluorescence staining for CEPI-17-CL4 cells was strongly positive for keratins (K)8, K18, and K19 and vimentin; weakly positive for K3, K13, and K17; and negative for K4, K7, and K14. Expression of cytokines (interleukin [IL]-1alpha, IL-1beta, IL-6, IL-8, tumor necrosis factor-alpha, and IL-ra), growth factors (transforming growth factor [TGF]-alpha, epidermal growth factors [EGF], EGF receptor [EGFR], TGF-beta1, TGF-beta2, and platelet-derived growth factor-beta) and cytochrome P450 enzymes (1A1, 2C, 2E1, and 3A5) was similar in CEPI-17-CL4 cells and human corneal epithelial samples obtained in biopsy. The CEPI-17-CL4 cells were metabolically competent for enzymes glutathione S-transferase, quinone reductase, aflatoxin aldehyde reductase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. CONCLUSIONS: The CEPI-17-CL4 cells are truly immortal and express an extensive array of cytokines, growth factors, and metabolic enzymes that resemble the original tissue. These characteristics, which remain stable up to high passage, will allow reproducible, mechanistic studies on toxicity, inflammation, and wound healing.

Human corneal epithelial cell functional responses to inflammatory agents and their antagonists.

PURPOSE: To investigate the epithelial nature of primary and SV40 virus-immortalized human corneal epithelial (CEPI) cells and to study a variety of functional responses to some key inflammatory agents (bradykinin [BK], histamine, and platelet-activating factor [PAF]) and their antagonists in these cells. METHODS: Primary CEPI (P-CEPI) and clone 4 of the SV40 virus-immortalized (CEPI-17-CL4) cells were analyzed for their interaction with several monoclonal antibodies selective for various cytokeratins to define their immunocytochemical characteristics and phenotypic traits. Both cell types were tested for their ability to respond to BK, histamine, and PAF and their antagonists, using the production of [3H]inositol phosphates ([3H]IPs) as an index of receptor activation. The ability of BK, PAF, and histamine to stimulate cytokine release and the induction of mRNA for matrix metalloproteinase-1 (MMP-1) were also studied using enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction techniques, respectively. RESULTS: P-CEPI and CEPI-17-CL4 cells were both shown to possess the epithelial cell cytokeratins labeled with AE1 and AE3 antibodies. The potencies (EC50s) of BK, histamine, and PAF were similar for stimulating [3H]IPs production in P-CEPI and CEPI-17-CL4 cells: BK = 2.27 to 2.99 nM, PAF = 17.1 to 18.26 nM, and histamine = 1.65 to 5.74 microM (all n = 3 to 6). Both cell types also responded similarly to receptor-selective antagonists for BK, PAF, and histamine (Hoe-140: Ki = 10.1 to 11.9 nM; PCA-4248: Ki = 315 to 421 nM; triprolidine: Ki = 0.8 to 4.76 nM; all n = 5 to 10). Histamine (100 microM) and interleukin-1alpha (IL-1alpha, 10 ng/ml) significantly stimulated IL-6 and granulocyte macrophage colony-stimulating factor release, and histamine, BK, and PAF stimulated the mRNA for MMP-1 in these cells. CONCLUSIONS: These studies have shown that the primary and immortalized human corneal epithelial cells express functional BK (a B2 subtype), histamine (an H1 subtype), and PAF receptors and exhibit very similar immunocytochemical, signal transduction, and pharmacological properties. Therefore, the CEPI-17-CL4 cells (currently at passage 220) appear to provide a useful representative in vitro model system to study the physiological and pathologic aspects of the human corneal epithelium.

Does repetitive physical loading inhibit radial growth in female gymnasts?

OBJECTIVE: Stress-related injuries to the distal radius have been noted in female gymnasts with potential for resultant premature closure and abnormal growth at this site. The purpose of this study was comprehensively to review and critically to appraise the available literature to examine the evidence related to this question: does repetitive physical loading inhibit growth of the radius in female gymnasts? DATA SOURCES: MEDLINE and SPORT Discuss were searched from 1975 to the present by using "gymnast" in combination with injury, growth plate, epiphyseal, and ulnar variance. Additional references were retrieved from the bibliographies of the retrieved articles. STUDY SELECTION: All descriptive and analytic studies that included data related to stress-related injuries affecting the distal radius of competitive female gymnasts were included. Conclusions regarding the effects of gymnastics training on radial growth of female gymnasts were limited to data from case reports, clinical series, cross-sectional studies, and descriptive cohort studies. Data from relevant experimental animal studies also were included. DATA EXTRACTION AND SYNTHESIS: In reviewing the literature, particular attention was paid to the relative strengths of the different study designs. From these data, information associated with growth inhibition at the distal radius was examined. MAIN RESULTS: The descriptive research reviewed included clinical, cross-sectional, and cohort studies that establish the existence of stress-related injuries affecting one or more constituent parts of the epiphyseal-physeal-metaphyseal (EPM) complex of the distal radius, symptomatic ulna-radial-length difference (URLD), and distal radius physeal arrest among female gymnasts. Five cross-sectional studies showed radiographic abnormalities consistent with distal radius physeal-stress reaction in 10-85% of gymnasts studied. Two cross-sectional studies indicated "abnormal" positive URLD in 8-20% of wrists radiographed. Four cross-sectional studies showed significant correlations between training intensity and URLD, suggesting a dose-response relation. Three cross-sectional studies indicate greater URLD in gymnasts compared with nongymnasts. Radiographic evidence of distal radius physeal arrest involving physically immature female gymnasts is presented in four studies (two clinical series, one cross-sectional, and one descriptive cohort). In animal studies, prolonged physical training has also been shown to inhibit or stop growth in weight-bearing long bones. However, there were no rigorous studies (i.e., randomized control trials or analytic cohorts) examining the question. CONCLUSION: The results of this critical review of the scientific literature support the plausibility of stress-related distal radius physeal arrest with secondary URLD. However, the strength of evidence is inadequate to be conclusive.

Pharmacological analysis of mast cell mediator and neurotransmitter receptors coupled to adenylate cyclase and phospholipase C on immunocytochemically-defined human conjunctival epithelial cells.

We sought to establish and immunocytochemically characterize primary cultures of human conjunctival epithelial (HCE) cells, and to determine the types of receptors coupled to adenylate cyclase (AC) and phospholipase C (PLC) present on them which may be stimulated following allergic or inflammatory provocation of the tissue. HCE cells possessed the key epithelial cell surface cytokeratins AE1, AE3 and AE5. Signal transduction studies (n > or = 3), using agonists and antagonists, revealed the presence of beta 2-adrenergic (isoproterenol EC50 = 5.2 nM), prostaglandin E2 (EC50 = 168 nM) and vasoactive intestinal peptide (EC50 = 0.69 nM) receptors positively coupled to AC in HCE cells. Bradykinin (EC50 = 0.83 nM), platelet activating factor (EC50 = 4.5 nM), leukotriene C4 (EC50 = 300 nM) and histamine1 (EC50 = 3.1 microM) receptors were coupled to PLC (n = 3 for each). These data suggest that HCE cells in vivo may represent target cells for mast cell mediators and certain neurotransmitters which are released into the tear-film upon allergic provocation of the conjunctiva.

Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.

Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.

Pinning down skin infections: diagnosis, treatment, and prevention in wrestlers.

Wrestling fosters skin infections such as herpes simplex, tinea corporis, and impetigo. Visual examination often suggests the diagnosis, but some lesions, like late-stage herpes, can mimic other conditions, like impetigo; laboratory studies therefore may be required. Drug therapy can mitigate an infection and help prevent recurrence. In addition, physicians must know when to disqualify a wrestler and how to prevent an outbreak through measures like good hygiene and immediate diagnosis.

Structure-based design of HIV protease inhibitors: 5,6-dihydro-4-hydroxy-2-pyrones as effective, nonpeptidic inhibitors.

From a broad screening program, the 4-hydroxycoumarin phenprocoumon (I) was previously identified as a lead template with HIV protease inhibitory activity. The crystal structure of phenprocoumon/HIV protease complex initiated a structure-based design effort that initially identified the 4-hydroxy-2-pyrone U-96988 (II) as a first-generation clinical candidate for the potential treatment of HIV infection. Based upon the crystal structure of the 4-hydroxy-2-pyrone III/HIV protease complex, a series of analogues incorporating a 5,6-dihydro-4-hydroxy-2-pyrone template were studied. It was recognized that in addition to having the required pharmacophore (the 4-hydroxy group with hydrogen-bonding interaction with the two catalytic aspartic acid residues and the lactone moiety replacing the ubiquitous water molecule in the active site), these 5,6-dihydro-4-hydroxy-2-pyrones incorporated side chains at the C-6 position that appropriately extended into the S1' and S2' subsites of the enzyme active site. The crystal structures of a number of representative 5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV protease were also determined to provide better understanding of the interaction between the enzyme and these inhibitors to aid the structure-based drug design effort. The crystal structures of the ligands in the enzyme active site did not always agree with the conformations expected from experience with previous pyrone inhibitors. This is likely due to the increased flexibility of the dihydropyrone ring. From this study, compound XIX exhibited reasonably high enzyme inhibitory activity (Ki = 15 nM) and showed antiviral activity (IC50 = 5 microM) in the cell-culture assay. This result provided a research direction which led to the discovery of active 5,6-dihydro-4-hydroxy-2-pyrones as potential agents for the treatment of HIV infection.

Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships.

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.

Meningococcemia: heading off a killer.

Meningococcemia is a dangerous disease requiring early and aggressive treatment to prevent a potentially lethal outcome. It often occurs in relatively closed groups, including sports camps and athletic teams. A high index of suspicion must be maintained when evaluating acute febrile illness, particularly in people younger than 20. Treatment includes antibiotics and intensive care support. Prophylaxis in the intimately exposed population, and education about signs and symptoms of the disease for more peripheral contacts are critical for successfully limiting any outbreak.

A systematic approach to health surveillance in the workplace.

This paper reviews the range of health surveillance activities which can be utilized in the workplace by occupational health professionals for assessing fitness for work and contributing to the prevention of occupational illness and promotion of good health. The systematic approach described categorizes health surveillance procedures into occupational or non-occupational, risk-based or unfocused, and as primary, secondary or tertiary preventive measures. All categories of health surveillance are currently being practised to some extent, but the type of surveillance may not match the needs of the workplace in some situation. In order to aid health professionals in deciding which procedures should be implemented, recommendations based on an assessment of health risks are made. The key proposal is to establish a minimum level of periodic health surveillance for all workers based on a targeted lifestyle health risk assessment and a structured health questionnaire. Additional procedures can then be added sequentially as appropriate to manage any health risks in the workplace. The role of the unfocused periodic general medical examination is discussed in the context of the systematic approach and allows occupational professionals to critically appraise its usefulness.